Pyrazole magl inhibitors

ABSTRACT

Provided herein are pyrazole compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful as modulators of MAGL. Furthermore, the subject compounds and compositions are useful for the treatment of pain.

CROSS-REFERENCE

This application claims benefit of U.S. Provisional Application No.62/510,223, filed on May 23, 2017, which is herein incorporated byreference in its entirety.

BACKGROUND

Monoacylglycerol lipase (MAGL) is an enzyme responsible for hydrolyzingendocannabinoids such as 2-AG (2-arachidonoylglycerol), an arachidonatebased lipid, in the nervous system. Fatty acid amide hydrolase (FAAH) isanother enzyme responsible for hydrolyzing endocannabinoids such asanandamide.

BRIEF SUMMARY OF THE INVENTION

This disclosure provides, for example, compounds and compositions whichare modulators of MAGL, and their use as medicinal agents, processes fortheir preparation, and pharmaceutical compositions that includedisclosed compounds as at least one active ingredient. The disclosurealso provides for the use of disclosed compounds as medicaments and/orin the manufacture of medicaments for the inhibition of MAGL activity inwarm-blooded animals such as humans.

In one aspect is a compound of Formula (I):

wherein:

-   -   R¹ is —N(R²)C(O)R¹⁵ or —N(H)SO₂R¹⁵;    -   R² is H or C₁₋₆alkyl;    -   R³ is

-   -   A is N or C(H);    -   X is —O—, —N(R¹⁶)—, or —CH₂N(R¹⁶)CH₂—;    -   Y is —CH₂— or —C(O)—;    -   Z is —S—, —O—, or —N(R²⁰)—;    -   R⁴ is H, halogen, —OR⁷, C₁₋₆alkyl, C₁₋₆alkyl-OH, C₂₋₆alkenyl,        C₂₋₆alkynyl, —O—C₃₋₈cycloalkyl, —O—C₃₋₈cycloalkyl-OH,        —N(H)—C₁₋₆alkyl-CO₂H, —SO₂R¹⁷, —CO₂R⁸, —C(O)NR⁸R⁹,        C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl,        wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   R⁵ is H, —CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkoxy, or phenyl;    -   R⁶ is H, halogen, or C₁₋₆alkyl;    -   R⁷ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl, wherein        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   each R⁸ and each R⁹ are independently selected from H and        C₁₋₆alkyl; or R⁸ and R⁹ together with the nitrogen to which they        are attached are combined to form a heterocycloalkyl ring;    -   R¹⁰ is —O—C₁₋₆haloalkyl, —O—C₁₋₆alkyl-CO₂H, —O—C₃₋₈cycloalkyl,        —O—C₃₋₈cycloalkyl-CO₂H, —N(H)—C₁₋₆alkyl-CO₂H, or —SO₂R¹⁷;    -   R¹² is H, halogen, or C₁₋₆alkyl;    -   R¹³ is H or C₁₋₆alkyl;    -   each R¹⁴ is independently selected from halogen, —OH, oxo,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, —C₁₋₆alkyl-OH,        C₃₋₈cycloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹, —C(O)—C₁₋₆alkyl,        —C(O)—C₁₋₆alkyl-OH, —SO₂—C₁₋₆alkyl, —N(R⁸)SO₂—C₁₋₆alkyl, and        —N(R⁸)C(O)—C₁₋₆alkyl;    -   R¹⁵ is C₁₋₆alkyl or C₃₋₈cycloalkyl;    -   R¹⁶ is H, C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, or —CH₂CO₂H;    -   R¹⁷ is C₁₋₆alkyl or C₃₋₈cycloalkyl;    -   R¹⁸ and R¹⁹ are independently selected from H and C₁₋₆alkyl,        wherein R¹⁸ and R¹⁹ are not both H;    -   R²⁰ is H or C₁₋₆alkyl;    -   v is 0 or 1;    -   n is 0 or 1;    -   m is 0 or 1;    -   p is 0, 1, or 2;    -   q is 0, 1, or 2; and    -   w is 1 or 2;    -   or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or        pharmaceutically acceptable salt thereof.

In some embodiments is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein m is 1, n is 1, p is 1, and w is 1. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein m is 0, n is 1, p is 1, and w is 2. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein m is 1, n is 1, p is 0, and w is 1. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein A is C(H). In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein A is N. In someembodiments is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein m is 1, n is 1, q is 1, and p is 1. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein m is 0, n is 1, q is 2, and p is 1. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein m is 1, n is 1, q is 0, and p is 2. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein m is 1, n is 1, q is 1, and p is 0. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein Z is —S—. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein Z is —N(H)—. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein Y is —CH₂—. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein Y is —C(O)—. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁶ is H. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein Z is —S—. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein Z is —N(H)—. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹³ is H. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is H. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹³ is H. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹³ is —CH₃. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is H. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein v is 0. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein v is 1. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein X is —O—. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein X is —N(CH₃)—. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein A is C(H). In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein A is N. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹⁸ is C₁₋₆alkyl. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁸is —CH₃ and R¹⁹ is H. In another embodiment is a compound of Formula(I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁹ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹⁸ is H and R¹⁹ is —CH₃. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁶ isH. In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is halogen, —OR⁷, C₁₋₆alkyl-OH,—N(H)—C₁₋₆alkyl-CO₂H, C₂₋₆alkynyl, C₁₋₆haloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl,wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, orC₁₋₉heteroaryl are optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is halogen, —OR⁷, —N(H)—C₁₋₆alkyl-CO₂H,C₁₋₆haloalkyl, —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, orC₁₋₉heteroaryl, wherein C₂₋₉heterocycloalkyl or C₁₋₉heteroaryl areoptionally substituted with 1 or 2 R¹⁴. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ ishalogen. In another embodiment is a compound of Formula (I), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —Cl. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ isC₁₋₆haloalkyl. In another embodiment is a compound of Formula (I), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —CF₃. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)—C₁₋₆alkyl-CO₂H. In another embodiment is a compound of Formula(I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁷ is unsubstituted C₃₋₈cycloalkyl or C₆₋₁₀aryloptionally substituted with halogen. In another embodiment is a compoundof Formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁴ isC₂₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is an unsubstituted C₂₋₉heterocycloalkyl. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is C₂₋₉heterocycloalkyl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₁₋₉heteroaryl optionally substituted with 1or 2 R¹⁴. In another embodiment is a compound of Formula (I), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is an unsubstituted C₁₋₉heteroaryl.In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is —C(O)NH₂. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹⁰ is —O—C₁₋₆alkyl-CO₂H. In another embodiment isa compound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁰is —OCH₂CO₂H or —OCH₂CH₂CH₂CO₂H. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁰ is—N(H)—C₁₋₆alkyl-CO₂H. In another embodiment is a compound of Formula(I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁰ is —N(H)CH₂CO₂H,—N(H)CH₂CH₂CO₂H, or —N(H)CH₂CH₂CH₂CO₂H. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁶ isH. In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is H, —CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,or C₁₋₆haloalkoxy. In another embodiment is a compound of Formula (I),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is H. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is halogen. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is —Cl. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is C₁₋₆haloalkyl. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵ is—CF₃. In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹ is —N(R²)C(O)R¹⁵. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R² isH. In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹⁵ is C₁₋₆alkyl. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁵is —CH₃. In another embodiment is a compound of Formula (I), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹⁵ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹⁵ is —CH₃.

In another embodiment is a pharmaceutical composition comprising acompound of Formula (I) described herein, or a solvate, hydrate,tautomer, N-oxide, or a pharmaceutically acceptable salt thereof, and atleast one pharmaceutically acceptable excipient.

In another embodiment is a method of treating pain in a patient in needthereof, comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula (I) described herein, or asolvate, hydrate, tautomer, N-oxide, or a pharmaceutically acceptablesalt thereof. In another embodiment is a method of treating neuropathicpain in a patient in need thereof, comprising administering to thepatient a therapeutically effective amount of a compound of Formula (I)described herein, or a solvate, hydrate, tautomer, N-oxide, or apharmaceutically acceptable salt thereof. In another embodiment is amethod of treating inflammatory pain in a patient in need thereof,comprising administering to the patient a therapeutically effectiveamount of a compound of Formula (I) described herein, or a solvate,hydrate, tautomer, N-oxide, or a pharmaceutically acceptable saltthereof.

In another embodiment is a method of treating a disease or disorder in apatient comprising administering to the patient in need thereof atherapeutically effective amount of a compound of Formula (I) describedherein, or a solvate, hydrate, tautomer, N-oxide, or a pharmaceuticallyacceptable salt thereof, wherein the disease is selected from migraine,epilepsy/seizure disorder, neuromyelitis optica (NMO), Tourettesyndrome, persistent motor tic disorder, persistent vocal tic disorder,and abdominal pain associated with irritable bowel syndrome. In anotherembodiment is a method of treating migraine in a patient in needthereof, comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula (I) described herein, or asolvate, hydrate, tautomer, N-oxide, or a pharmaceutically acceptablesalt thereof. In another embodiment is a method of treatingepilepsy/seizure disorder in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I) described herein, or a solvate, hydrate,tautomer, N-oxide, or a pharmaceutically acceptable salt thereof. Inanother embodiment is a method of treating neuromyelitis optica (NMO) ina patient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound of Formula (I) describedherein, or a solvate, hydrate, tautomer, N-oxide, or a pharmaceuticallyacceptable salt thereof. In another embodiment is a method of treatingTourette syndrome in a patient in need thereof, comprising administeringto the patient a therapeutically effective amount of a compound ofFormula (I) described herein, or a solvate, hydrate, tautomer, N-oxide,or a pharmaceutically acceptable salt thereof. In another embodiment isa method of treating persistent motor tic disorder in a patient in needthereof, comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula (I) described herein, or asolvate, hydrate, tautomer, N-oxide, or a pharmaceutically acceptablesalt thereof. In another embodiment is a method of treating persistentvocal tic disorder in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I) described herein, or a solvate, hydrate,tautomer, N-oxide, or a pharmaceutically acceptable salt thereof. Inanother embodiment is a method of treating abdominal pain associatedwith irritable bowel syndrome in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I) described herein, or a solvate, hydrate,tautomer, N-oxide, or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

This disclosure is directed, at least in part, to modulators orinhibitors of MAGL. For example, provided herein are compounds capableof inhibiting MAGL.

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof. When ranges are used herein for physicalproperties, such as molecular weight, or chemical properties, such aschemical formulae, all combinations and subcombinations of ranges andspecific embodiments therein are intended to be included. The term“about” when referring to a number or a numerical range means that thenumber or numerical range referred to is an approximation withinexperimental variability (or within statistical experimental error), andthus the number or numerical range varies between 1% and 15% of thestated number or numerical range. The term “comprising” (and relatedterms such as “comprise” or “comprises” or “having” or “including”) isnot intended to exclude that which in other certain embodiments, forexample, an embodiment of any composition of matter, composition,method, or process, or the like, described herein, may “consist of” or“consist essentially of” the described features.

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). C₁-C_(x)refers to the number of carbon atoms that make up the moiety to which itdesignates (excluding optional substituents).

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Alkyl” or “alkylene” refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises one to six carbon atoms (e.g., C₁-C₆alkyl). In other embodiments, an alkyl comprises one to five carbonatoms (e.g., C₁-C₅ alkyl). In other embodiments, an alkyl comprises oneto four carbon atoms (e.g., C₁-C₄ alkyl). In other embodiments, an alkylcomprises one to three carbon atoms (e.g., C₁-C₃ alkyl). In otherembodiments, an alkyl comprises one to two carbon atoms (e.g., C₁-C₂alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g.,C₁ alkyl). In other embodiments, an alkyl comprises five to fifteencarbon atoms (e.g., C₅-C₁₅ alkyl). In other embodiments, an alkylcomprises five to eight carbon atoms (e.g., C₅-C₈ alkyl). In otherembodiments, an alkyl comprises two to five carbon atoms (e.g., C₂-C₅alkyl). In other embodiments, an alkyl comprises three to five carbonatoms (e.g., C₃-C₅ alkyl). In other embodiments, the alkyl group isselected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl(iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl),2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tent-butyl), and 1-pentyl(n-pentyl). The alkyl is attached to the rest of the molecule by asingle bond. Unless stated otherwise specifically in the specification,an alkyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(f), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(f),—OC(O)—NR^(a)R^(f), —N(R^(a))C(O)R^(f), —N(R^(a))S(O)_(t)R^(f) (where tis 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(f) (where tis 1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a)is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R^(f) isindependently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl, or heteroarylalkyl.

“Alkoxy” refers to a radical bonded through an oxygen atom of theformula —O-alkyl, where alkyl is an alkyl chain as defined above.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms. In other embodiments, an alkenyl comprises two to fourcarbon atoms. The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unlessstated otherwise specifically in the specification, an alkenyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(f), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(f), —OC(O)—NR^(a)R^(f),—N(R^(a))C(O)R^(f), —N(R^(a))S(O)_(t)R^(f) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(f) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R^(f) isindependently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl, or heteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, having from two to twelve carbonatoms. In certain embodiments, an alkynyl comprises two to eight carbonatoms. In other embodiments, an alkynyl has two to four carbon atoms.The alkynyl is attached to the rest of the molecule by a single bond,for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Unless stated otherwise specifically in the specification, analkynyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(f), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(f),—OC(O)—NR^(a)R^(f), —N(R^(a))C(O)R^(f), —N(R^(a))S(O)_(t)R^(f) (where tis 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(f) (where tis 1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a)is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R^(f) isindependently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl, or heteroarylalkyl.

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from six to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin andnaphthalene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, haloalkyl, cyano, nitro,aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl,heteroaryl, heteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,heteroaryl, or heteroarylalkyl, each R^(b) is independently a directbond or a straight or branched alkylene or alkenylene chain, and R^(c)is a straight or branched alkylene or alkenylene chain.

“Aryloxy” refers to a radical bonded through an oxygen atom of theformula —O-aryl, where aryl is as defined above.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, methylene, ethylene,and the like. The alkylene chain part of the aralkyl radical isoptionally substituted as described above for an alkylene chain. Thearyl part of the aralkyl radical is optionally substituted as describedabove for an aryl group.

“Aralkyloxy” refers to a radical bonded through an oxygen atom of theformula —O-aralkyl, where aralkyl is as defined above.

“Aralkenyl” refers to a radical of the formula R^(d)-aryl where R^(d) isan alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Cycloalkyl ” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which includes fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a cycloalkyl comprisesthree to ten carbon atoms. In other embodiments, a cycloalkyl comprisesfive to seven carbon atoms. The cycloalkyl is attached to the rest ofthe molecule by a single bond. Cycloalkyls are saturated, (i.e.,containing single C—C bonds only) or partially unsaturated (i.e.,containing one or more double bonds or triple bonds.) Examples ofmonocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certainembodiments, a cycloalkyl comprises three to eight carbon atoms (e.g.,C₃-C₈ cycloalkyl). In other embodiments, a cycloalkyl comprises three toseven carbon atoms (e.g., C₃-C₇ cycloalkyl). In other embodiments, acycloalkyl comprises three to six carbon atoms (e.g., C₃-C₆ cycloalkyl).In other embodiments, a cycloalkyl comprises three to five carbon atoms(e.g., C₃-C₅ cycloalkyl). In other embodiments, a cycloalkyl comprisesthree to four carbon atoms (e.g., C₃-C₄ cycloalkyl). A partiallyunsaturated cycloalkyl is also referred to as “cycloalkenyl.” Examplesof monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl,cycloheptenyl, and cyclooctenyl. Polycyclic cycloalkyl radicals include,for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl),norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and thelike. Unless stated otherwise specifically in the specification, theterm “cycloalkyl” is meant to include cycloalkyl radicals that areoptionally substituted by one or more substituents selected from alkyl,alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl,aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl,heteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, eachR^(b) is independently a direct bond or a straight or branched alkyleneor alkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above.

“Haloalkoxy” refers to an alkoxy radical, as defined above, that issubstituted by one or more halo radicals, as defined above.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Thealkyl part of the fluoroalkyl radical are optionally substituted asdefined above for an alkyl group.

“Heterocycloalkyl” refers to a stable 3- to 18-membered non-aromaticring radical that comprises two to twelve carbon atoms and from one tosix heteroatoms selected from nitrogen, oxygen and sulfur. Unless statedotherwise specifically in the specification, the heterocycloalkylradical is a monocyclic, bicyclic, tricyclic, or tetracyclic ringsystem, which include fused, spiro, or bridged ring systems. Theheteroatoms in the heterocycloalkyl radical are optionally oxidized. Oneor more nitrogen atoms, if present, are optionally quaternized. Theheterocycloalkyl radical is partially or fully saturated. In someembodiments, the heterocycloalkyl is attached to the rest of themolecule through any atom of the ring(s). Examples of suchheterocycloalkyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, the term “heterocycloalkyl” is meant to includeheterocycloalkyl radicals as defined above that are optionallysubstituted by one or more substituents selected from alkyl, alkenyl,alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl,aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl,heteroarylalkyl, —R ^(b)—OR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,heteroaryl, or heteroarylalkyl, each R^(b) is independently a directbond or a straight or branched alkylene or alkenylene chain, and R^(c)is a straight or branched alkylene or alkenylene chain.

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises one to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical is a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Unless stated otherwise specifically in the specification,the term “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo,cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl,heterocycloalkyl, heteroaryl, heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, eachR^(b) is independently a direct bond or a straight or branched alkyleneor alkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroaryloxy” refers to radical bonded through an oxygen atom of theformula —O-heteroaryl, where heteroaryl is as defined above.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

In some embodiments, the compounds disclosed herein contain one or moreasymmetric centers and thus give rise to enantiomers, diastereomers, andother stereoisomeric forms that are defined, in terms of absolutestereochemistry, as (R)- or (S)-. Unless stated otherwise, it isintended that all stereoisomeric forms of the compounds disclosed hereinare contemplated by this disclosure. When the compounds described hereincontain alkene double bonds, and unless specified otherwise, it isintended that this disclosure includes both E and Z geometric isomers(e.g., cis or trans.) Likewise, all possible isomers, as well as theirracemic and optically pure forms, and all tautomeric forms are alsointended to be included. The term “geometric isomer” refers to E or Zgeometric isomers (e.g., cis or trans) of an alkene double bond. Theterm “positional isomer” refers to structural isomers around a centralring, such as ortho-, meta-, and para-isomers around a benzene ring.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Incertain embodiments, the compounds presented herein exist as tautomers.In circumstances where tautomerization is possible, a chemicalequilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

“Optional” or “optionally” means that a subsequently described event orcircumstance may or may not occur and that the description includesinstances when the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical are or are not substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the pyrazolecompounds described herein is intended to encompass any and allpharmaceutically suitable salt forms. Preferred pharmaceuticallyacceptable salts of the compounds described herein are pharmaceuticallyacceptable acid addition salts, and pharmaceutically acceptable baseaddition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basiccompounds are prepared by contacting the free base forms with asufficient amount of the desired acid to produce the salt.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. In some embodiments, pharmaceutically acceptable baseaddition salts are formed with metals or amines, such as alkali andalkaline earth metals or organic amines. Salts derived from inorganicbases include, but are not limited to, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminumsalts, and the like. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, for example,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine,hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline,N-methylglucamine, glucosamine, methylglucamine, theobromine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins, and thelike. See Berge et al., supra.

As used herein, “treatment” or “treating ” or “palliating” or“ameliorating” are used interchangeably herein. These terms refer to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient is still afflicted with the underlying disorder. Forprophylactic benefit, the compositions are administered to a patient atrisk of developing a particular disease, or to a patient reporting oneor more of the physiological symptoms of a disease, even though adiagnosis of this disease has not been made.

Compounds

The compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (Ik), (Il), or (Im) described herein which aremodulators of MAGL. In some embodiments, the compounds are inhibitors ofMAGL. The compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If),(Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im) described herein, andcompositions comprising these compounds, are useful for the treatment ofpain. In some embodiments, the compounds of Formula (I), (Ia), (Ib),(Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im)described herein, and compositions comprising these compounds, areuseful for the treatment of pain, multiple sclerosis, Alzheimer'sdisease, and/or inflammatory bowel disease.

In some embodiments is a compound of Formula (I):

wherein:

-   -   R¹ is —N(R²)C(O)R¹⁵ or —N(H)SO₂R¹⁵;    -   R² is H or C₁₋₆alkyl;    -   R³ is

-   -   A is N or C(H);    -   X is —O—, —N(R¹⁶)—, or —CH₂N(R¹⁶)CH₂—;    -   Y is —CH₂— or —C(O)—;    -   Z is —S—, —O—, or —N(R²⁰)—;    -   R⁴ is H, halogen, —OR⁷, C₁₋₆alkyl, C₁₋₆alkyl-OH, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, —O—C₃₋₈cycloalkyl,        —O—C₃₋₈cycloalkyl-OH, —N(H)—C₁₋₆alkyl-CO₂H, —SO₂R¹⁷, —CO₂R⁸,        —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl,        wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   R⁵ is H, —CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy,        or phenyl;    -   R⁶ is H, halogen, or C₁₋₆alkyl;    -   R⁷ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl, wherein        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   each R⁸ and each R⁹ are independently selected from H and        C₁₋₆alkyl; or R⁸ and R⁹ together with the nitrogen to which they        are attached are combined to form a heterocycloalkyl ring;    -   R¹⁰ is —O—C₁₋₆haloalkyl, —O—C₁₋₆alkyl-CO₂H, —O—C₃₋₈cycloalkyl,        —O—C₃₋₈cycloalkyl-CO₂H, —N(H)—C₁₋₆alkyl-CO₂H, or —SO₂R¹⁷;    -   R12 is H, halogen, or C₁₋₆alkyl;

R¹³ is H or C₁₋₆alkyl;

-   -   each R¹⁴ is independently selected from halogen, —OH, oxo,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, —C₁₋₆alkyl-OH,        C₃₋₈cycloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹, —C(O)—C₁₋₆alkyl,        —C(O)—C₁₋₆alkyl-OH, —SO₂—C₁₋₆alkyl, —N(R⁸)SO₂—C₁₋₆alkyl, and        —N(R⁸)C(O)—C₁₋₆alkyl;    -   R¹⁵ is C₁₋₆alkyl or C₃₋₈cycloalkyl;    -   R¹⁶ is H, C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, or —CH₂CO₂H;    -   R¹⁷ is C₁₋₆alkyl or C₃₋₈cycloalkyl;    -   R¹⁸ and R¹⁰ are independently selected from H and C₁₋₆alkyl,        wherein R¹⁸ and R¹⁹ are not both H;    -   R²⁰ is H or C₁₋₆alkyl;    -   v is 0 or 1;    -   n is 0 or 1;    -   m is 0 or 1;    -   p is 0, 1, or 2;    -   q is 0, 1, or 2; and    -   w is 1 or 2;    -   or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or        pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹ is —N(R²)C(O)R¹⁵. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹ is—N(R²)C(O)R¹⁵ and R² is H. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula (I), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ and R¹⁵ is —CH₃. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(H)C(O)R¹⁵ and R¹⁵ is C₃₋₈cycloalkyl. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² is C₁₋₆alkyl. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² is —CH₃. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₁₋₆alkyl. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is —CH₃. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₃₋₈cycloalkyl. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(H)SO₂R¹⁵. In another embodiment is a compoundof Formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵and R¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula(I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (I), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl.

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹⁸ is C₁₋₆alkyl. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁸is C₁₋₆alkyl and R¹⁹ is H. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁸ is —CH₃ and R¹⁹ isH. In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹⁹ is C₁₋₆alkyl. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁸is H and R¹⁹ is C₁₋₆alkyl. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁸ is H and R¹⁹ is—CH₃. In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹⁸ and R¹⁹ are C₁₋₆alkyl. In another embodimentis a compound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁸and R¹⁹ are —CH₃.

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein Z is —S—. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein Z is —O—. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein Z is —N(R²⁰)—. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein Z is —N(H)—. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is H and R¹³ is H. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is C₁₋₆alkyl and R¹³ is H. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is —CH₃ and R¹³ isH. In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is H and R¹³ is C₁₋₆alkyl. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is H and R¹³ is —CH₃. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is C₁₋₆alkyl and R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹² is —CH₃ and R¹³is —CH₃.

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein m is 1, n is 1, p is 1, and w is 1. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein m is 0, n is 1, p is 1, and w is 2. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein m is 1, n is 1, p is 0, and w is 1. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein A is C(H). In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein A is N. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein Z is —S—. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein Z is —O—. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein Z is —N(R²⁰)—. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein Z is —N(H)—. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein Z is —N(CH₃)—. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein Y is —CH₂—. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein Y is —C(O)—. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is1, and p is 1. In another embodiment is a compound of Formula (I), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein m is 0, n is 1, q is 2, and p is 1. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein m is 1, n is 1, q is 0, and p is 2. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein m is 1, n is 1, q is 1, and p is 0. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein m is 0, n is 0, q is 2, and p is 1. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is H and R¹³ is H. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is C₁₋₆alkyl and R¹³ is H. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is —CH₃ and R¹³ isH. In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is H and R¹³ is C₁₋₆alkyl. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is H and R¹³ is —CH₃. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is C₁₋₆alkyl and R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹² is —CH₃ and R¹³is —CH₃.

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is C₁₋₆alkyl and R¹³ is H. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃ and R¹³ is H. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is H and R¹³ is C₁₋₆alkyl. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is H and R¹³ is—CH₃. In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is C₁₋₆alkyl and R¹³ is C₁₋₆alkyl. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃ and R¹³ is —CH₃. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein X is —O—. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein X is —N(R¹⁶)—. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein X is —N(H)—. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein X is —N(CH₃)—. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein X is —CH₂N(R¹⁶)CH₂—. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein X is—CH₂N(H)CH₂—. In another embodiment is a compound of Formula (I), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein X is —CH₂N(CH₃)CH₂—. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein A is N. In another embodiment is a compound of Formula(I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein A is C(H). In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein v is 0. In another embodiment is a compound of Formula(I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein v is 1. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is halogen, —OR⁷, C₁₋₆alkyl-OH,—N(H)—C₁₋₆alkyl-CO₂H, C₂₋₆alkynyl, C₁₋₆haloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl,wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, orC₁₋₉heteroaryl are optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is halogen, —OR⁷, —N(H)—C₁₋₆alkyl-CO₂H,C₁₋₆haloalkyl, —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, orC₁₋₉heteroaryl, wherein C₂₋₉heterocycloalkyl or C₁₋₉heteroaryl areoptionally substituted with 1 or 2 R¹⁴. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ ishalogen. In another embodiment is a compound of Formula (I), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —Cl. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ isC₁₋₆haloalkyl. In another embodiment is a compound of Formula (I), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —CF₃. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)—C₁₋₆alkyl-CO₂H. In another embodiment is a compound of Formula(I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —N(H)CH₂CO₂H. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —N(H)CH₂CH₂CO₂H. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)CH₂CH₂CH₂CO₂H. In another embodiment is a compound of Formula (I),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —C(O)NR⁸R⁹. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —C(O)NH₂. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is C₃₋₈cycloalkyl.In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is —OR⁷. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isunsubstituted C₃₋₈cycloalkyl or C₆₋₁₀aryl optionally substituted withhalogen. In another embodiment is a compound of Formula (I), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is unsubstitutedC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (I), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is phenyl optionallysubstituted with halogen. In another embodiment is a compound of Formula(I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with halogen. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with —Cl. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₂₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is an unsubstituted C₂₋₉heterocycloalkyl. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is C₂₋₉heterocycloalkyl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₄₋₅heterocycloalkyl optionally substitutedwith 1 or 2 R¹⁴, wherein the C₄₋₅heterocycloalkyl is a monocyclicheterocycloalkyl selected from pyrrolidine, piperidine, piperazine, andmorpholine. In another embodiment is a compound of Formula (I), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is C₅₋₉heterocycloalkyl optionallysubstituted with 1 or 2 R¹⁴, wherein the C₅₋₉heterocycloalkyl is abicyclic heterocycloalkyl. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₅₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴, wherein theC₅₋₉heterocycloalkyl is a spirocyclic heterocycloalkyl. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₁₋₉heteroaryl optionally substituted with 1or 2 R¹⁴. In another embodiment is a compound of Formula (I), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is an unsubstituted C₁₋₉heteroaryl.In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl optionally substituted with 1or 2 R¹⁴, wherein the C₂₋₉heteroaryl is selected from pyrrole, furan,thiophene, thiazole, pyrazole, oxazole, oxadiazole, thiadiazole,pyridine, pyrimidine, pyrazine, indole, benzothiophene, benzofuran, andimidazopyridine. In another embodiment is a compound of Formula (I), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is H, CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, orC₁₋₆haloalkoxy. In another embodiment is a compound of Formula (I), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁵ is H. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵ is—CN. In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is halogen. In another embodiment is a compoundof Formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁵ is —Cl. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —F. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —CH₃. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkyl.In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —CF₃. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkoxy.In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —OCF₃. In another embodiment is a compoundof Formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁶ is H. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is halogen. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is —Cl. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —F. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —CH₃.

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is

In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹⁰ is —O—C₁₋₆alkyl-CO₂H. In another embodiment isa compound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁰is —OCH₂CO₂H. In another embodiment is a compound of Formula (I), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹⁰ is —OCH₂CH₂CO₂H. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹⁰ is —OCH₂CH₂CH₂CO₂H. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁰is —N(H)—C₁₋₆alkyl-CO₂H. In another embodiment is a compound of Formula(I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁰ is —N(H)CH₂CO₂H.In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹⁰ is —N(H)CH₂CH₂CO₂H. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁰is —N(H)CH₂CH₂CH₂CO₂H. In another embodiment is a compound of Formula(I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁰ is—O—C₁₋₆haloalkyl. In another embodiment is a compound of Formula (I), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹⁰ is —OCF₃. In another embodiment isa compound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁰is —O—C₃₋₈cycloalkyl. In another embodiment is a compound of Formula(I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁰ is—O—C₃₋₈cycloalkyl-CO₂H. In another embodiment is a compound of Formula(I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁰ is —SO₂R¹⁷. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹⁰ is —SO₂R¹⁷ and R¹⁷ is C₁₋₆alkyl. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹⁰ is —SO₂R¹⁷ and R¹⁷ is —CH₃. In another embodimentis a compound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁰is —SO₂R¹⁷ and R¹⁷ is C₃₋₈cycloalkyl. In another embodiment is acompound of Formula (I), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵ isH, CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆haloalkoxy. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is H. In another embodiment is a compound of Formula(I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is —CN. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is halogen. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is —Cl. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —F. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —CH₃. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkyl.In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —CF₃. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkoxy.In another embodiment is a compound of Formula (I), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —OCF₃. In another embodiment is a compoundof Formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁶ is H. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is halogen. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is —Cl. In anotherembodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —F. In another embodiment is a compound ofFormula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (I), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —CH₃.

In another embodiment is a compound of Formula (I) having the structureof Formula (Ia):

wherein:

-   -   R¹ is —N(R²)C(O)R¹⁵ or —N(H)SO₂R¹⁵;    -   R² is H or C₁₋₆alkyl;    -   R⁴ is H, halogen, —OR⁷, C ₁₋₆ alkyl, C₁₋₆alkyl-OH, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, —O—C₃₋₈cycloalkyl,        —O—C₃₋₈cycloalkyl-OH, —N(H)—C₁₋₆alkyl-CO₂H, —SO₂R¹⁷, —CO₂R⁸,        —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl,        wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   R⁵ is H, —CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy,        or phenyl;    -   R⁶ is H, halogen, or C₁₋₆alkyl;    -   R⁷ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl, wherein        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   each R⁸ and each R⁹ are independently selected from H and        C₁₋₆alkyl; or R⁸ and R⁹ together with the nitrogen to which they        are attached are combined to form a heterocycloalkyl ring;    -   R¹² is H, halogen, or C₁₋₆alkyl;    -   R¹³ is H or C₁₋₆alkyl;    -   each R¹⁴ is independently selected from halogen, —OH, oxo,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, —C₁₋₆alkyl-OH,        C₃₋₈cycloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹, —C(O)—C₁₋₆alkyl,        —C(O)—C₁₋₆alkyl-OH, —SO₂—C₁₋₆alkyl, —N(R⁸)SO₂—C₁₋₆alkyl, and        —N(R⁸)C(O)—C₁₋₆alkyl;    -   R¹⁵ is C₁₋₆alkyl or C₃₋₈cycloalkyl; and    -   R¹⁷ is C₁₋₆alkyl or C₃₋₈cycloalkyl;    -   or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or        pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula (Ia), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, having the structure

In another embodiment is a compound of Formula (Ia), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, having the structure

In another embodiment is a compound of Formula (Ia), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹ is —N(R²)C(O)R¹⁵. In another embodiment is acompound of Formula (Ia), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹ is—N(R²)C(O)R¹⁵ and R² is H. In another embodiment is a compound ofFormula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula (Ia),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Ia), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Ia), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² isC₁₋₆alkyl. In another embodiment is a compound of Formula (Ia), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² is —CH₃. Inanother embodiment is a compound of Formula (Ia), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₁₋₆alkyl. In anotherembodiment is a compound of Formula (Ia), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is —CH₃. In anotherembodiment is a compound of Formula (Ia), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₃₋₈cycloalkyl. Inanother embodiment is a compound of Formula (Ia), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(H)SO₂R¹⁵. In another embodiment is a compoundof Formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵and R¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula(Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Ia), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl.

In another embodiment is a compound of Formula (Ia), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is halogen, —OR⁷, C₁₋₆alkyl-OH,—N(H)—C₁₋₆alkyl-CO₂H, C₂₋₆alkynyl, C₁₋₆haloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl,wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, orC₁₋₉heteroaryl are optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (Ia), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is halogen, —OR⁷, —N(H)—C₁₋₆alkyl-CO₂H,C₁₋₆haloalkyl, —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, orC₁₋₉heteroaryl, wherein C₂₋₉heterocycloalkyl or C₁₋₉heteroaryl areoptionally substituted with 1 or 2 R¹⁴. In another embodiment is acompound of Formula (Ia), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ ishalogen. In another embodiment is a compound of Formula (Ia), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —Cl. In another embodiment is acompound of Formula (Ia), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ isC₁₋₆haloalkyl. In another embodiment is a compound of Formula (Ia), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —CF₃. In another embodiment is acompound of Formula (Ia), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)—C₁₋₆alkyl-CO₂H. In another embodiment is a compound of Formula(Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —N(H)CH₂CO₂H. Inanother embodiment is a compound of Formula (Ia), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —N(H)CH₂CH₂CO₂H. In another embodiment is acompound of Formula (Ia), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)CH₂CH₂CH₂CO₂H. In another embodiment is a compound of Formula (Ia),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —C(O)NR⁸R⁹. Inanother embodiment is a compound of Formula (Ia), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —C(O)NH₂. In another embodiment is a compound ofFormula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is C₃₋₈cycloalkyl.In another embodiment is a compound of Formula (Ia), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is —OR⁷. In another embodiment is a compound ofFormula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isunsubstituted C₃₋₈cycloalkyl or C₆₋₁₀aryl optionally substituted withhalogen. In another embodiment is a compound of Formula (Ia), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is unsubstitutedC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Ia), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is phenyl optionallysubstituted with halogen. In another embodiment is a compound of Formula(Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with halogen. In another embodiment is a compound ofFormula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with —Cl. In another embodiment is a compound ofFormula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₂₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (Ia), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is an unsubstituted C₂₋₉heterocycloalkyl. In anotherembodiment is a compound of Formula (Ia), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is C₂₋₉heterocycloalkyl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (Ia), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₄₋₅heterocycloalkyl optionally substitutedwith 1 or 2 R¹⁴, wherein the C₄₋₅heterocycloalkyl is a monocyclicheterocycloalkyl selected from pyrrolidine, piperidine, piperazine, andmorpholine. In another embodiment is a compound of Formula (Ia), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is C₅₋₉heterocycloalkyl optionallysubstituted with 1 or 2 R¹⁴, wherein the C₅₋₉heterocycloalkyl is abicyclic heterocycloalkyl. In another embodiment is a compound ofFormula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₅₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴, wherein theC₅₋₉heterocycloalkyl is a spirocyclic heterocycloalkyl. In anotherembodiment is a compound of Formula (Ia), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is

In another embodiment is a compound of Formula (Ia), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₁₋₉heteroaryl optionally substituted with 1or 2 R¹⁴. In another embodiment is a compound of Formula (Ia), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is an unsubstituted C₁₋₉heteroaryl.In another embodiment is a compound of Formula (Ia), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (Ia), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl optionally substituted with 1or 2 R¹⁴, wherein the C₂₋₉heteroaryl is selected from pyrrole, furan,thiophene, thiazole, pyrazole, oxazole, oxadiazole, thiadiazole,pyridine, pyrimidine, pyrazine, indole, benzothiophene, benzofuran, andimidazopyridine. In another embodiment is a compound of Formula (Ia), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is

In another embodiment is a compound of Formula (Ia), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is H, CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, orC₁₋₆haloalkoxy. In another embodiment is a compound of Formula (Ia), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁵ is H. In another embodiment is acompound of Formula (Ia), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵ is—CN. In another embodiment is a compound of Formula (Ia), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is halogen. In another embodiment is a compoundof Formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁵ is —Cl. Inanother embodiment is a compound of Formula (Ia), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —F. In another embodiment is a compound ofFormula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ia), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —CH₃. In another embodiment is a compound ofFormula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkyl.In another embodiment is a compound of Formula (Ia), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —CF₃. In another embodiment is a compound ofFormula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkoxy.In another embodiment is a compound of Formula (Ia), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —OCF₃. In another embodiment is a compoundof Formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁶ is H. In anotherembodiment is a compound of Formula (Ia), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is halogen. In another embodiment is a compound ofFormula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is —Cl. In anotherembodiment is a compound of Formula (Ia), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —F. In another embodiment is a compound ofFormula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ia), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —CH₃.

In another embodiment is a compound of Formula (Ia), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is H. In another embodiment is a compound ofFormula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ia), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃. In another embodiment is a compound ofFormula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹³ is H. In anotherembodiment is a compound of Formula (Ia), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹³ is —CH₃. Inanother embodiment is a compound of Formula (Ia), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is H and R¹³ is H. In another embodiment is acompound of Formula (Ia), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is H and R¹³ is C₁₋₆alkyl. In another embodiment is a compound ofFormula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is H and R¹³ is—CH₃. In another embodiment is a compound of Formula (Ia), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is C₁₋₆alkyl and R¹³ is H. In anotherembodiment is a compound of Formula (Ia), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃ and R¹³ is H. In another embodiment is acompound of Formula (Ia), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is C₁₋₆alkyl and R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹² is —CH₃ and R¹³is —CH₃.

In another embodiment is a compound of Formula (I) having the structureof Formula (Ib):

wherein:

-   -   R¹ is —N(R²)C(O)R¹⁵ or —N(H)SO₂R¹⁵;    -   R² is H or C₁₋₆alkyl;    -   Z is —S—, —O—, or —N(R²⁰)—;    -   R⁴ is H, halogen, —OR⁷, C ₁₋₆alkyl, C ₁₋₆alkyl-OH, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, —O—C₃₋₈cycloalkyl,        —O—C₃₋₈cycloalkyl-OH, —N(H)—C₁₋₆alkyl-CO₂H, —SO₂R¹⁷, —CO₂R⁸,        —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl,        wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   R⁵ is H, —CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkoxy, or phenyl;    -   R⁶ is H, halogen, or C₁₋₆alkyl;

R⁷ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,C₆₋₁₀aryl, or C₁₋₉heteroaryl, wherein C₂₋₉heterocycloalkyl, C₆₋₁₀aryl,or C₁₋₉heteroaryl are optionally substituted with 1 or 2 R¹⁴;

-   -   each R⁸ and each R⁹ are independently selected from H and        C₁₋₆alkyl; or R⁸ and R⁹ together with the nitrogen to which they        are attached are combined to form a heterocycloalkyl ring;    -   R¹² is H, halogen, or C₁₋₆alkyl;    -   R¹³ is H or C₁₋₆alkyl;    -   each R¹⁴ is independently selected from halogen, —OH, oxo,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, —C₁₋₆alkyl-OH,        C₃₋₈cycloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹, —C(O)—C₁₋₆alkyl,        —C(O)—C₁₋₆alkyl-OH, —SO₂—C₁₋₆alkyl, —N(R⁸)SO₂—C₁₋₆alkyl, and        —N(R⁸)C(O)—C₁₋₆alkyl;    -   R¹⁵ is C₁₋₆alkyl or C₃₋₈cycloalkyl;    -   R¹⁷ is C₁₋₆alkyl or C₃₋₈cycloalkyl; and    -   R²⁰ is H or C₁₋₆alkyl;    -   or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or        pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula (Ib), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, having the structure

In another embodiment is a compound of Formula (Ib), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, having the structure

In another embodiment is a compound of Formula (Ib), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein Z is —S—. In another embodiment is a compound ofFormula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein Z is —O—. In anotherembodiment is a compound of Formula (Ib), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein Z is —N(R²⁰)—. In another embodiment is a compound ofFormula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein Z is —N(H)—. Inanother embodiment is a compound of Formula (Ib), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein Z is —N(CH₃)—.

In another embodiment is a compound of Formula (Ib), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹ is —N(R²)C(O)R¹⁵. In another embodiment is acompound of Formula (Ib), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹ is—N(R²)C(O)R¹⁵ and R² is H. In another embodiment is a compound ofFormula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula (Ib),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Ib), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Ib), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² isC₁₋₆alkyl. In another embodiment is a compound of Formula (Ib), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² is —CH₃. Inanother embodiment is a compound of Formula (Ib), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₁₋₆alkyl. In anotherembodiment is a compound of Formula (Ib), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is —CH₃. In anotherembodiment is a compound of Formula (Ib), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₃₋₈cycloalkyl. Inanother embodiment is a compound of Formula (Ib), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(H)SO₂R¹⁵. In another embodiment is a compoundof Formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵and R¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula(Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Ib), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl.

In another embodiment is a compound of Formula (Ib), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is halogen, —OR⁷, C₁₋₆alkyl-OH, —N(H)—C₁₋₆alkyl-CO₂H, C₂₋₆alkynyl, C₁₋₆haloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl,wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, orC₁₋₉heteroaryl are optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (Ib), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is halogen, —OR⁷, —N(H)—C₁₋₆alkyl-CO₂H,C₁₋₆haloalkyl, —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, orC₁₋₉heteroaryl, wherein C₂₋₉heterocycloalkyl or C₁₋₉heteroaryl areoptionally substituted with 1 or 2 R¹⁴. In another embodiment is acompound of Formula (Ib), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ ishalogen. In another embodiment is a compound of Formula (Ib), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —Cl. In another embodiment is acompound of Formula (Ib), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ isC₁₋₆haloalkyl. In another embodiment is a compound of Formula (Ib), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —CF₃. In another embodiment is acompound of Formula (Ib), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)—C₁₋₆alkyl-CO₂H. In another embodiment is a compound of Formula(Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —N(H)CH₂CO₂H. Inanother embodiment is a compound of Formula (Ib), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —N(H)CH₂CH₂CO₂H. In another embodiment is acompound of Formula (Ib), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)CH₂CH₂CH₂CO₂H. In another embodiment is a compound of Formula (Ib),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —C(O)NR⁸R⁹. Inanother embodiment is a compound of Formula (Ib), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —C(O)NH₂. In another embodiment is a compound ofFormula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is C₃₋₈cycloalkyl.In another embodiment is a compound of Formula (Ib), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is —OR⁷. In another embodiment is a compound ofFormula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isunsubstituted C₃₋₈cycloalkyl or C₆₋₁₀aryl optionally substituted withhalogen. In another embodiment is a compound of Formula (Ib), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is unsubstitutedC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Ib), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is phenyl optionallysubstituted with halogen. In another embodiment is a compound of Formula(Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with halogen. In another embodiment is a compound ofFormula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with —Cl. In another embodiment is a compound ofFormula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₂₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (Ib), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is an unsubstituted C₂₋₉heterocycloalkyl. In anotherembodiment is a compound of Formula (Ib), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is C₂₋₉heterocycloalkyl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (Ib), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₄₋₅heterocycloalkyl optionally substitutedwith 1 or 2 R¹⁴, wherein the C₄₋₅heterocycloalkyl is a monocyclicheterocycloalkyl selected from pyrrolidine, piperidine, piperazine, andmorpholine. In another embodiment is a compound of Formula (Ib), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is C₅₋₉heterocycloalkyl optionallysubstituted with 1 or 2 R¹⁴, wherein the C₅₋₉heterocycloalkyl is abicyclic heterocycloalkyl. In another embodiment is a compound ofFormula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₅₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴, wherein theC₅₋₉heterocycloalkyl is a spirocyclic heterocycloalkyl. In anotherembodiment is a compound of Formula (Ib), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is

In another embodiment is a compound of Formula (Ib), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₁₋₉heteroaryl optionally substituted with 1or 2 R¹⁴. In another embodiment is a compound of Formula (Ib), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is an unsubstituted C₁₋₉heteroaryl.In another embodiment is a compound of Formula (Ib), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (Ib), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl optionally substituted with 1or 2 R¹⁴, wherein the C₂₋₉heteroaryl is selected from pyrrole, furan,thiophene, thiazole, pyrazole, oxazole, oxadiazole, thiadiazole,pyridine, pyrimidine, pyrazine, indole, benzothiophene, benzofuran, andimidazopyridine. In another embodiment is a compound of Formula (Ib), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is

In another embodiment is a compound of Formula (Ib), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is H, CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, orC₁₋₆haloalkoxy. In another embodiment is a compound of Formula (Ib), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁵ is H. In another embodiment is acompound of Formula (Ib), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵ is—CN. In another embodiment is a compound of Formula (Ib), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is halogen. In another embodiment is a compoundof Formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁵ is —Cl. Inanother embodiment is a compound of Formula (Ib), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —F. In another embodiment is a compound ofFormula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ib), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —CH₃. In another embodiment is a compound ofFormula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkyl.In another embodiment is a compound of Formula (Ib), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —CF₃. In another embodiment is a compound ofFormula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkoxy.In another embodiment is a compound of Formula (Ib), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —OCF₃. In another embodiment is a compoundof Formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁶ is H. In anotherembodiment is a compound of Formula (Ib), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is halogen. In another embodiment is a compound ofFormula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is —Cl. In anotherembodiment is a compound of Formula (Ib), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —F. In another embodiment is a compound ofFormula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ib), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —CH₃.

In another embodiment is a compound of Formula (Ib), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is H. In another embodiment is a compound ofFormula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ib), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃. In another embodiment is a compound ofFormula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹³ is H. In anotherembodiment is a compound of Formula (Ib), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹³ is —CH₃. Inanother embodiment is a compound of Formula (Ib), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is H and R¹³ is H. In another embodiment is acompound of Formula (Ib), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is H and R¹³ is C₁₋₆alkyl. In another embodiment is a compound ofFormula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is H and R¹³ is—CH₃. In another embodiment is a compound of Formula (Ib), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is C₁₋₆alkyl and R¹³ is H. In anotherembodiment is a compound of Formula (Ib), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃ and R¹³ is H. In another embodiment is acompound of Formula (Ib), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is C₁₋₆alkyl and R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹² is —CH₃ and R¹³is —CH₃.

In another embodiment is a compound of Formula (I) having the structureof Formula (Ic):

wherein:

-   -   R¹ is —N(R²)C(O)R¹⁵ or —N(H)SO₂R¹⁵;    -   R² is H or C₁₋₆alkyl;    -   Z is —S—, —O—, or —N(R²⁰)—;

R⁴ is H, halogen, —OR⁷, C₁₋₆alkyl, C₁₋₆alkyl-OH, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, —O—C₃₋₈cycloalkyl, —O—C₃₋₈cycloalkyl-OH,—N(H)—C₁₋₆alkyl-CO₂H, —SO₂R¹⁷, —CO₂R⁸, —C(O)NR⁸R⁹, C₃₋₈cycloalkyl,C₂₋₉heterocycloalkyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl,C₁₋₉heteroaryl, wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,—C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl areoptionally substituted with 1 or 2 R¹⁴;

-   R⁵ is H, —CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy, or    phenyl;    -   R⁷ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl, wherein        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   each R⁸ and each R⁹ are independently selected from H and        C₁₋₆alkyl; or R⁸ and R⁹ together with the nitrogen to which they        are attached are combined to form a heterocycloalkyl ring;    -   R¹² is H, halogen, or C₁₋₆alkyl;    -   R¹³ is H or C₁₋₆alkyl;    -   each R¹⁴ is independently selected from halogen, —OH, oxo,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, —C₁₋₆alkyl-OH,        C₃₋₈cycloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹, —C(O)—C₁₋₆alkyl,        —C(O)—C₁₋₆alkyl-OH, —SO₂—C₁₋₆alkyl, —N(R⁸)SO₂—C₁₋₆alkyl, and        —N(R⁸)C(O)—C₁₋₆alkyl;    -   R¹⁵ is C₁₋₆alkyl or C₃₋₈cycloalkyl;    -   R¹⁷ is C₁₋₆alkyl or C₃₋₈cycloalkyl; and    -   R²⁰ is H or C₁₋₆alkyl;    -   or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or        pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula (Ic), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, having the structure

In another embodiment is a compound of Formula (Ic), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, having the structure

In another embodiment is a compound of Formula (Ic), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein Z is —S—. In another embodiment is a compound ofFormula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein Z is —O—. In anotherembodiment is a compound of Formula (Ic), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein Z is —N(R²⁰)—. In another embodiment is a compound ofFormula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein Z is —N(H)—. Inanother embodiment is a compound of Formula (Ic), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein Z is —N(CH₃)—.

In another embodiment is a compound of Formula (Ic), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹ is —N(R²)C(O)R¹⁵. In another embodiment is acompound of Formula (Ic), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹ is—N(R²)C(O)R¹⁵ and R² is H. In another embodiment is a compound ofFormula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula (Ic),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Ic), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Ic), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² isC₁₋₆alkyl. In another embodiment is a compound of Formula (Ic), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² is —CH₃. Inanother embodiment is a compound of Formula (Ic), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₁₋₆alkyl. In anotherembodiment is a compound of Formula (Ic), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is —CH₃. In anotherembodiment is a compound of Formula (Ic), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₃₋₈cycloalkyl. Inanother embodiment is a compound of Formula (Ic), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(H)SO₂R¹⁵. In another embodiment is a compoundof Formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵and R¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula(Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Ic), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R² is —N(H)SO₂R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl.

In another embodiment is a compound of Formula (Ic), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is halogen, —OR⁷, C₁₋₆alkyl-OH,—N(H)—C₁₋₆alkyl-CO₂H, C₂₋₆alkynyl, C₁₋₆haloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl,wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, orC₁₋₉heteroaryl are optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (Ic), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is halogen, —OR⁷, —N(H)—C₁₋₆alkyl-CO₂H,C₁₋₆haloalkyl, —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, orC₁₋₉heteroaryl, wherein C₂₋₉heterocycloalkyl or C₁₋₉heteroaryl areoptionally substituted with 1 or 2 R¹⁴. In another embodiment is acompound of Formula (Ic), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ ishalogen. In another embodiment is a compound of Formula (Ic), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —Cl. In another embodiment is acompound of Formula (Ic), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ isC₁₋₆haloalkyl. In another embodiment is a compound of Formula (Ic), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —CF₃. In another embodiment is acompound of Formula (Ic), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)—C₁₋₆alkyl-CO₂H. In another embodiment is a compound of Formula(Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —N(H)CH₂CO₂H. Inanother embodiment is a compound of Formula (Ic), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —N(H)CH₂CH₂CO₂H. In another embodiment is acompound of Formula (Ic), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)CH₂CH₂CH₂CO₂H. In another embodiment is a compound of Formula (Ic),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —C(O)NR⁸R⁹. Inanother embodiment is a compound of Formula (Ic), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —C(O)NH₂. In another embodiment is a compound ofFormula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is C₃₋₈cycloalkyl.In another embodiment is a compound of Formula (Ic), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is —OR⁷. In another embodiment is a compound ofFormula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isunsubstituted C₃₋₈cycloalkyl or C₆₋₁₀aryl optionally substituted withhalogen. In another embodiment is a compound of Formula (Ic), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is unsubstitutedC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Ic), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is phenyl optionallysubstituted with halogen. In another embodiment is a compound of Formula(Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with halogen. In another embodiment is a compound ofFormula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with —Cl. In another embodiment is a compound ofFormula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₂₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (Ic), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is an unsubstituted C₂₋₉heterocycloalkyl. In anotherembodiment is a compound of Formula (Ic), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is C₂₋₉heterocycloalkyl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (Ic), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₄₋₅heterocycloalkyl optionally substitutedwith 1 or 2 R¹⁴, wherein the C₄₋₅heterocycloalkyl is a monocyclicheterocycloalkyl selected from pyrrolidine, piperidine, piperazine, andmorpholine. In another embodiment is a compound of Formula (Ic), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is C₅₋₉heterocycloalkyl optionallysubstituted with 1 or 2 R¹⁴, wherein the C₅₋₉heterocycloalkyl is abicyclic heterocycloalkyl. In another embodiment is a compound ofFormula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₅₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴, wherein theC₅₋₉heterocycloalkyl is a spirocyclic heterocycloalkyl. In anotherembodiment is a compound of Formula (Ic), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is

In another embodiment is a compound of Formula (Ic), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₁₋₉heteroaryl optionally substituted with 1or 2 R¹⁴. In another embodiment is a compound of Formula (Ic), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is an unsubstituted C₁₋₉heteroaryl.In another embodiment is a compound of Formula (Ic), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (Ic), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl optionally substituted with 1or 2 R¹⁴, wherein the C₂₋₉heteroaryl is selected from pyrrole, furan,thiophene, thiazole, pyrazole, oxazole, oxadiazole, thiadiazole,pyridine, pyrimidine, pyrazine, indole, benzothiophene, benzofuran, andimidazopyridine. In another embodiment is a compound of Formula (Ic), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is

In another embodiment is a compound of Formula (Ic), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is H, CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, orC₁₋₆haloalkoxy. In another embodiment is a compound of Formula (Ic), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁵ is H. In another embodiment is acompound of Formula (Ic), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵ is—CN. In another embodiment is a compound of Formula (Ic), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is halogen. In another embodiment is a compoundof Formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁵ is —Cl. Inanother embodiment is a compound of Formula (Ic), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —F. In another embodiment is a compound ofFormula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ic), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —CH₃. In another embodiment is a compound ofFormula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkyl.In another embodiment is a compound of Formula (Ic), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —CF₃. In another embodiment is a compound ofFormula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkoxy.In another embodiment is a compound of Formula (Ic), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —OCF₃.

In another embodiment is a compound of Formula (Ic), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is H. In another embodiment is a compound ofFormula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ic), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃. In another embodiment is a compound ofFormula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹³ is H. In anotherembodiment is a compound of Formula (Ic), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹³ is —CH₃. Inanother embodiment is a compound of Formula (Ic), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is H and R¹³ is H. In another embodiment is acompound of Formula (Ic), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is H and R¹³ is C₁₋₆alkyl. In another embodiment is a compound ofFormula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is H and R¹³ is—CH₃. In another embodiment is a compound of Formula (Ic), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is C₁₋₆alkyl and R¹³ is H. In anotherembodiment is a compound of Formula (Ic), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃ and R¹³ is H. In another embodiment is acompound of Formula (Ic), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is C₁₋₆alkyl and R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹² is —CH₃ and R¹³is —CH₃.

In another embodiment is a compound of Formula (I) having the structureof Formula (Id):

wherein:

-   -   R¹ is —N(R²)C(O)R¹⁵ or —N(H)SO₂R¹⁵;    -   R² is H or C₁₋₆alkyl;    -   A is N or C(H);    -   Y is —CH₂— or —C(O)—;    -   R⁴ is H, halogen, —OR⁷, C ₁₋₆alkyl, C ₁₋₆alkyl-OH, C₂₋₆alkenyl,        C ₂₋₆ alkynyl, C₁₋₆haloalkyl, —O—C₃₋₈cycloalkyl,        —O—C₃₋₈cycloalkyl-OH, —N(H)—C ₁₋₆ alkyl-CO₂H, —SO₂R¹⁷, —CO₂R⁸,        —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl,        wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   R⁵ is H, —CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy,        or phenyl;    -   R⁶ is H, halogen, or C₁₋₆alkyl;    -   R⁷ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl, wherein        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   each R⁸ and each R⁹ are independently selected from H and        C₁₋₆alkyl; or R⁸ and R⁹ together with the nitrogen to which they        are attached are combined to form a heterocycloalkyl ring;    -   R¹² is H, halogen, or C₁₋₆alkyl;    -   R¹³ is H or C₁₋₆alkyl;    -   each R¹⁴ is independently selected from halogen, —OH, oxo,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, —C₁₋₆alkyl-OH,        C₃₋₈cycloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹, —C(O)—C₁₋₆alkyl,        —C(O)—C₁₋₆alkyl-OH, —SO₂—C₁₋₆alkyl, —N(R⁸)SO₂—C₁₋₆alkyl, and        —N(R⁸)C(O)—C₁₋₆alkyl;    -   R¹⁵ is C₁₋₆alkyl or C₃₋₈cycloalkyl;    -   R¹⁷ is C₁₋₆alkyl or C₃₋₈cycloalkyl;    -   n is 0 or 1;    -   m is 0 or 1;    -   p is 0, 1, or 2; and    -   w is 1 or 2;    -   or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or        pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula (Id), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹ is —N(R²)C(O)R¹⁵. In another embodiment is acompound of Formula (Id), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹ is—N(R²)C(O)R¹⁵ and R² is H. In another embodiment is a compound ofFormula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula (Id),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Id), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Id), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² isC₁₋₆alkyl. In another embodiment is a compound of Formula (Id), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² is —CH₃. Inanother embodiment is a compound of Formula (Id), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₁₋₆alkyl. In anotherembodiment is a compound of Formula (Id), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is —CH₃. In anotherembodiment is a compound of Formula (Id), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₃₋₈cycloalkyl. Inanother embodiment is a compound of Formula (Id), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(H)SO₂R¹⁵. In another embodiment is a compoundof Formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵and R¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula(Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Id), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl.

In another embodiment is a compound of Formula (Id), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein m is 1, n is 1, p is 1, and w is 1. In anotherembodiment is a compound of Formula (Id), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein m is 0, n is 1, p is 1, and w is 2. In anotherembodiment is a compound of Formula (Id), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein m is 1, n is 1, p is 0, and w is 1.

In another embodiment is a compound of Formula (Id), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein A is C(H). In another embodiment is a compound ofFormula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein A is N.

In another embodiment is a compound of Formula (Id), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein Y is —CH₂—. In another embodiment is a compound ofFormula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein Y is —C(O)—.

In another embodiment is a compound of Formula (Id), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is H. In another embodiment is a compound ofFormula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Id), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃. In another embodiment is a compound ofFormula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹³ is H. In anotherembodiment is a compound of Formula (Id), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹³ is —CH₃. Inanother embodiment is a compound of Formula (Id), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is H and R¹³ is H. In another embodiment is acompound of Formula (Id), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is H and R¹³ is C₁₋₆alkyl. In another embodiment is a compound ofFormula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is H and R¹³ is—CH₃. In another embodiment is a compound of Formula (Id), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is C₁₋₆alkyl and R¹³ is H. In anotherembodiment is a compound of Formula (Id), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃ and R¹³ is H. In another embodiment is acompound of Formula (Id), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is C₁₋₆alkyl and R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹² is —CH₃ and R¹³is —CH₃.

In another embodiment is a compound of Formula (Id), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is halogen, —OR⁷, C₁₋₆alkyl-OH,—N(H)—C₁₋₆alkyl-CO₂H, C₂₋₆alkynyl, C₁₋₆haloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl,wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, orC₁₋₉heteroaryl are optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (Id), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is halogen, —OR⁷, —N(H)—C₁₋₆alkyl-CO₂H,C₁₋₆haloalkyl, —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, orC₁₋₉heteroaryl, wherein C₂₋₉heterocycloalkyl or C₁₋₉heteroaryl areoptionally substituted with 1 or 2 R¹⁴. In another embodiment is acompound of Formula (Id), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ ishalogen. In another embodiment is a compound of Formula (Id), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —Cl. In another embodiment is acompound of Formula (Id), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ isC₁₋₆haloalkyl. In another embodiment is a compound of Formula (Id), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —CF₃. In another embodiment is acompound of Formula (Id), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)—C₁₋₆alkyl-CO₂H. In another embodiment is a compound of Formula(Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —N(H)CH₂CO₂H. Inanother embodiment is a compound of Formula (Id), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —N(H)CH₂CH₂CO₂H. In another embodiment is acompound of Formula (Id), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)CH₂CH₂CH₂CO₂H. In another embodiment is a compound of Formula (Id),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —C(O)NR⁸R⁹. Inanother embodiment is a compound of Formula (Id), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —C(O)NH₂. In another embodiment is a compound ofFormula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is C₃₋₈cycloalkyl.In another embodiment is a compound of Formula (Id), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is —OR⁷. In another embodiment is a compound ofFormula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isunsubstituted C₃₋₈cycloalkyl or C₆₋₁₀aryl optionally substituted withhalogen. In another embodiment is a compound of Formula (Id), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is unsubstitutedC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Id), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is phenyl optionallysubstituted with halogen. In another embodiment is a compound of Formula(Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with halogen. In another embodiment is a compound ofFormula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with —Cl. In another embodiment is a compound ofFormula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₂₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (Id), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is an unsubstituted C₂₋₉heterocycloalkyl. In anotherembodiment is a compound of Formula (Id), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is C₂₋₉heterocycloalkyl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (Id), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₄₋₅heterocycloalkyl optionally substitutedwith 1 or 2 R¹⁴, wherein the C₄₋₅heterocycloalkyl is a monocyclicheterocycloalkyl selected from pyrrolidine, piperidine, piperazine, andmorpholine. In another embodiment is a compound of Formula (Id), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is C₅₋₉heterocycloalkyl optionallysubstituted with 1 or 2 R¹⁴, wherein the C₅₋₉heterocycloalkyl is abicyclic heterocycloalkyl. In another embodiment is a compound ofFormula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₅₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴, wherein theC₅₋₉heterocycloalkyl is a spirocyclic heterocycloalkyl. In anotherembodiment is a compound of Formula (Id), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is

In another embodiment is a compound of Formula (Id), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₁₋₉heteroaryl optionally substituted with 1or 2 R¹⁴. In another embodiment is a compound of Formula (Id), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is an unsubstituted C₁₋₉heteroaryl.In another embodiment is a compound of Formula (Id), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (Id), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl optionally substituted with 1or 2 R¹⁴, wherein the C₂₋₉heteroaryl is selected from pyrrole, furan,thiophene, thiazole, pyrazole, oxazole, oxadiazole, thiadiazole,pyridine, pyrimidine, pyrazine, indole, benzothiophene, benzofuran, andimidazopyridine. In another embodiment is a compound of Formula (Id), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is

In another embodiment is a compound of Formula (Id), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is H, CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, orC₁₋₆haloalkoxy. In another embodiment is a compound of Formula (Id), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁵ is H. In another embodiment is acompound of Formula (Id), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵ is—CN. In another embodiment is a compound of Formula (Id), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is halogen. In another embodiment is a compoundof Formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁵ is —Cl. Inanother embodiment is a compound of Formula (Id), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —F. In another embodiment is a compound ofFormula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Id), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —CH₃. In another embodiment is a compound ofFormula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkyl.In another embodiment is a compound of Formula (Id), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —CF₃. In another embodiment is a compound ofFormula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkoxy.In another embodiment is a compound of Formula (Id), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —OCF₃. In another embodiment is a compoundof Formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁶ is H. In anotherembodiment is a compound of Formula (Id), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is halogen. In another embodiment is a compound ofFormula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is —Cl. In anotherembodiment is a compound of Formula (Id), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —F. In another embodiment is a compound ofFormula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Id), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —CH₃.

In another embodiment is a compound of Formula (I) having the structureof Formula (Ie):

wherein:

-   -   R¹ is —N(R²)C(O)R¹⁵ or —N(H)SO₂R¹⁵;    -   R² is H or C₁₋₆alkyl;    -   Y is —CH₂— or —C(O)—;    -   Z is —S—, —O—, or —N(R²⁰)—;    -   R⁴ is H, halogen, —OR⁷, C₁₋₆alkyl, C₁₋₆alkyl-OH, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, —O—C₃₋₈cycloalkyl,        —O—C₃₋₈cycloalkyl-OH, —N(H)—C₁₋₆alkyl-CO₂H, —SO₂R¹⁷, —CO₂R⁸,        —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl,        wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   R⁵ is H, —CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy,        or phenyl;    -   R⁶ is H, halogen, or C₁₋₆alkyl;    -   R⁷ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl, wherein        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   each R⁸ and each R⁹ are independently selected from H and        C₁₋₆alkyl; or R⁸ and R⁹ together with the nitrogen to which they        are attached are combined to form a heterocycloalkyl ring;    -   R¹² is H, halogen, or C₁₋₆alkyl;    -   R¹³ is H or C₁₋₆alkyl;    -   each R¹⁴ is independently selected from halogen, —OH, oxo,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, —C₁₋₆alkyl-OH,        C₃₋₈cycloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹, —C(O)—C₁₋₆alkyl,        —C(O)C₁₋₆alkyl-OH, —SO₂—C₁₋₆alkyl, —N(R⁸)SO₂—C₁₋₆alkyl, and        —N(R⁸)C(O)—C₁₋₆alkyl;    -   R¹⁵ is C₁₋₆alkyl or C₃₋₈cycloalkyl;    -   R¹⁷ is C₁₋₆alkyl or C₃₋₈cycloalkyl;    -   R²⁰ is H or C₁₋₆alkyl;    -   n is 0 or 1;    -   m is 0 or 1;    -   p is 0, 1, or 2; and    -   q is 0, 1, or 2;    -   or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or        pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula (Ie), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹ is —N(R²)C(O)R¹⁵. In another embodiment is acompound of Formula (Ie), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹ is—N(R²)C(O)R¹⁵ and R² is H. In another embodiment is a compound ofFormula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula (Ie),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Ie), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Ie), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² isC₁₋₆alkyl. In another embodiment is a compound of Formula (Ie), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² is —CH₃. Inanother embodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₁₋₆alkyl. In anotherembodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is —CH₃. In anotherembodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₃₋₈cycloalkyl. Inanother embodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(H)SO₂R¹⁵. In another embodiment is a compoundof Formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵and R¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula(Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Ie), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl.

In another embodiment is a compound of Formula (Ie), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein m is 1, n is 1, q is 1, and p is 1. In anotherembodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein m is 0, n is 1, q is 2, and p is 1. In anotherembodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein m is 1, n is 1, q is 0, and p is 2. In anotherembodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein m is 1, n is 1, q is 1, and p is 0. In anotherembodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein m is 0, n is 0, q is 2, and p is 1.

In another embodiment is a compound of Formula (Ie), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein Y is —CH₂—. In another embodiment is a compound ofFormula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein Y is —C(O)—.

In another embodiment is a compound of Formula (Ie), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein Z is —S—. In another embodiment is a compound ofFormula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein Z is —O—. In anotherembodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein Z is —N(R²⁰)—. In another embodiment is a compound ofFormula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein Z is —N(H)—. Inanother embodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein Z is —N(CH₃)—.

In another embodiment is a compound of Formula (Ie), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is H. In another embodiment is a compound ofFormula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃. In another embodiment is a compound ofFormula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹³ is H. In anotherembodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹³ is —CH₃. Inanother embodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is H and R¹³ is H. In another embodiment is acompound of Formula (Ie), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is H and R¹³ is C₁₋₆alkyl. In another embodiment is a compound ofFormula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is H and R¹³ is—CH₃. In another embodiment is a compound of Formula (Ie), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is C₁₋₆alkyl and R¹³ is H. In anotherembodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃ and R¹³ is H. In another embodiment is acompound of Formula (Ie), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is C₁₋₆alkyl and R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹² is —CH₃ and R¹³is —CH₃.

In another embodiment is a compound of Formula (Ie), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is halogen, —OR⁷, C₁₋₆alkyl-OH,—N(H)—C₁₋₆alkyl-CO₂H, C₂₋₆alkynyl, C₁₋₆haloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl,wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, orC₁₋₉heteroaryl are optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is halogen, —OR⁷, —N(H)—C₁₋₆alkyl-CO₂H,C₁₋₆haloalkyl, —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, orC₁₋₉heteroaryl, wherein C₂₋₉heterocycloalkyl or C₁₋₉heteroaryl areoptionally substituted with 1 or 2 R¹⁴. In another embodiment is acompound of Formula (Ie), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ ishalogen. In another embodiment is a compound of Formula (Ie), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —Cl. In another embodiment is acompound of Formula (Ie), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ isC₁₋₆haloalkyl. In another embodiment is a compound of Formula (Ie), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —CF₃. In another embodiment is acompound of Formula (Ie), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)—C₁₋₆alkyl-CO₂H. In another embodiment is a compound of Formula(Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —N(H)CH₂CO₂H. Inanother embodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —N(H)CH₂CH₂CO₂H. In another embodiment is acompound of Formula (Ie), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)CH₂CH₂CH₂CO₂H. In another embodiment is a compound of Formula (Ie),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —C(O)NR⁸R⁹. Inanother embodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —C(O)NH₂. In another embodiment is a compound ofFormula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is C₃₋₈cycloalkyl.In another embodiment is a compound of Formula (Ie), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is —OR⁷. In another embodiment is a compound ofFormula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isunsubstituted C₃₋₈cycloalkyl or C₆₋₁₀aryl optionally substituted withhalogen. In another embodiment is a compound of Formula (Ie), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is unsubstitutedC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Ie), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is phenyl optionallysubstituted with halogen. In another embodiment is a compound of Formula(Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with halogen. In another embodiment is a compound ofFormula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with —Cl. In another embodiment is a compound ofFormula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₂₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is an unsubstituted C₂₋₉heterocycloalkyl. In anotherembodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is C₂₋₉heterocycloalkyl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (Ie), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₄₋₅heterocycloalkyl optionally substitutedwith 1 or 2 R¹⁴, wherein the C₄₋₅heterocycloalkyl is a monocyclicheterocycloalkyl selected from pyrrolidine, piperidine, piperazine, andmorpholine. In another embodiment is a compound of Formula (Ie), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is C₅₋₉heterocycloalkyl optionallysubstituted with 1 or 2 R¹⁴, wherein the C₅₋₉heterocycloalkyl is abicyclic heterocycloalkyl. In another embodiment is a compound ofFormula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₅₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴, wherein theC₅₋₉heterocycloalkyl is a spirocyclic heterocycloalkyl. In anotherembodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is

In another embodiment is a compound of Formula (Ie), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₁₋₉heteroaryl optionally substituted with 1or 2 R¹⁴. In another embodiment is a compound of Formula (Ie), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is an unsubstituted C₁₋₉heteroaryl.In another embodiment is a compound of Formula (Ie), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (Ie), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl optionally substituted with 1or 2 R¹⁴, wherein the C₂₋₉heteroaryl is selected from pyrrole, furan,thiophene, thiazole, pyrazole, oxazole, oxadiazole, thiadiazole,pyridine, pyrimidine, pyrazine, indole, benzothiophene, benzofuran, andimidazopyridine. In another embodiment is a compound of Formula (Ie), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is

In another embodiment is a compound of Formula (Ie), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is H, CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, orC₁₋₆haloalkoxy. In another embodiment is a compound of Formula (Ie), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁵ is H. In another embodiment is acompound of Formula (Ie), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵ is—CN. In another embodiment is a compound of Formula (Ie), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is halogen. In another embodiment is a compoundof Formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁵ is —Cl. Inanother embodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —F. In another embodiment is a compound ofFormula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —CH₃. In another embodiment is a compound ofFormula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkyl.In another embodiment is a compound of Formula (Ie), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —CF₃. In another embodiment is a compound ofFormula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkoxy.In another embodiment is a compound of Formula (Ie), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —OCF₃. In another embodiment is a compoundof Formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁶ is H. In anotherembodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is halogen. In another embodiment is a compound ofFormula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is —Cl. In anotherembodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —F. In another embodiment is a compound ofFormula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ie), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —CH₃.

In another embodiment is a compound of Formula (I) having the structureof Formula (If):

wherein:

-   -   R¹ is —N(R²)C(O)R¹⁵ or —N(H)SO₂R¹⁵;    -   R² is H or C₁₋₆alkyl;    -   Y is —CH₂— or —C(O)—;    -   Z is —S—, —O—, or —N(R²⁰)—;    -   R⁴ is H, halogen, —OR⁷, C₁₋₆alkyl, C₁₋₆alkyl-OH, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, —O—C₃₋₈cycloalkyl,        —O—C₃₋₈cycloalkyl-OH, —N(H)—C₁₋₆alkyl-CO₂H, —SO₂R¹⁷, —CO₂R⁸,        —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl,        wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   R⁵ is H, —CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy,        or phenyl;    -   R⁷ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl, wherein        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   each R⁸ and each R⁹ are independently selected from H and        C₁₋₆alkyl; or R⁸ and R⁹ together with the nitrogen to which they        are attached are combined to form a heterocycloalkyl ring;    -   R¹² is H, halogen, or C₁₋₆alkyl;    -   R¹³ is H or C₁₋₆alkyl;    -   each R¹⁴ is independently selected from halogen, —OH, oxo,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, —C₁₋₆alkyl-OH,        C₃₋₈cycloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹, —C(O)—C₁₋₆alkyl,        —C(O)—C₁₋₆alkyl-OH, —SO₂—C₁₋₆alkyl, —N(R⁸)SO₂—C₁₋₆alkyl, and        —N(R⁸)C(O)—C₁₋₆alkyl;    -   R¹⁵ is C₁₋₆alkyl or C₃₋₈cycloalkyl;    -   R¹⁷ is C₁₋₆alkyl or C₃₋₈cycloalkyl;    -   R²⁰ is H or C₁₋₆alkyl;    -   n is 0 or 1;    -   m is 0 or 1;    -   p is 0, 1, or 2; and    -   q is 0, 1, or 2;    -   or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or        pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula (If), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹ is —N(R²)C(O)R¹⁵. In another embodiment is acompound of Formula (If), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹ is—N(R²)C(O)R¹⁵ and R² is H. In another embodiment is a compound ofFormula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula (If),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (If), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (If), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² isC₁₋₆alkyl. In another embodiment is a compound of Formula (If), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² is —CH₃. Inanother embodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₁₋₆alkyl. In anotherembodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is —CH₃. In anotherembodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₃₋₈cycloalkyl. Inanother embodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(H)SO₂R¹⁵. In another embodiment is a compoundof Formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵and R¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula(If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (If), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl.

In another embodiment is a compound of Formula (If), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein m is 1, n is 1, q is 1, and p is 1. In anotherembodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein m is 0, n is 1, q is 2, and p is 1. In anotherembodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein m is 1, n is 1, q is 0, and p is 2. In anotherembodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein m is 1, n is 1, q is 1, and p is 0. In anotherembodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein m is 0, n is 0, q is 2, and p is 1.

In another embodiment is a compound of Formula (If), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein Y is —CH₂—. In another embodiment is a compound ofFormula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein Y is —C(O)—.

In another embodiment is a compound of Formula (If), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein Z is —S—. In another embodiment is a compound ofFormula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein Z is —O—. In anotherembodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein Z is —N(R²⁰)—. In another embodiment is a compound ofFormula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein Z is —N(H)—. Inanother embodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein Z is —N(CH₃)—.

In another embodiment is a compound of Formula (If), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is H. In another embodiment is a compound ofFormula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃. In another embodiment is a compound ofFormula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹³ is H. In anotherembodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹³ is —CH₃. Inanother embodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is H and R¹³ is H. In another embodiment is acompound of Formula (If), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is H and R¹³ is C₁₋₆alkyl. In another embodiment is a compound ofFormula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is H and R¹³ is—CH₃. In another embodiment is a compound of Formula (If), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is C₁₋₆alkyl and R¹³ is H. In anotherembodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃ and R¹³ is H. In another embodiment is acompound of Formula (If), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is C₁₋₆alkyl and R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹² is —CH₃ and R¹³is —CH₃.

In another embodiment is a compound of Formula (If), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is halogen, —OR⁷, C₁₋₆ alkyl-OH,—N(H)—C₁₋₆alkyl-CO₂H, C₂₋₆alkynyl, C₁₋₆haloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl,wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, orC₁₋₉heteroaryl are optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is halogen, —OR⁷, —N(H)—C₁₋₆alkyl-CO₂H,C₁₋₆haloalkyl, —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, orC₁₋₉heteroaryl, wherein C₂₋₉heterocycloalkyl or C₁₋₉heteroaryl areoptionally substituted with 1 or 2 R¹⁴. In another embodiment is acompound of Formula (If), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ ishalogen. In another embodiment is a compound of Formula (If), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —Cl. In another embodiment is acompound of Formula (If), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ isC₁₋₆haloalkyl. In another embodiment is a compound of Formula (If), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —CF₃. In another embodiment is acompound of Formula (If), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)—C₁₋₆alkyl-CO₂H. In another embodiment is a compound of Formula(If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —N(H)CH₂CO₂H. Inanother embodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —N(H)CH₂CH₂CO₂H. In another embodiment is acompound of Formula (If), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)CH₂CH₂CH₂CO₂H. In another embodiment is a compound of Formula (If),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —C(O)NR⁸R⁹. Inanother embodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —C(O)NH₂. In another embodiment is a compound ofFormula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is C₃₋₈cycloalkyl.In another embodiment is a compound of Formula (If), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is —OR⁷. In another embodiment is a compound ofFormula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isunsubstituted C₃₋₈cycloalkyl or C₆₋₁₀aryl optionally substituted withhalogen. In another embodiment is a compound of Formula (If), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is unsubstitutedC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (If), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is phenyl optionallysubstituted with halogen. In another embodiment is a compound of Formula(If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with halogen. In another embodiment is a compound ofFormula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with —Cl. In another embodiment is a compound ofFormula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₂₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is an unsubstituted C₂₋₉heterocycloalkyl. In anotherembodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is C₂₋₉heterocycloalkyl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (If), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₄₋₅heterocycloalkyl optionally substitutedwith 1 or 2 R¹⁴, wherein the C₄₋₅heterocycloalkyl is a monocyclicheterocycloalkyl selected from pyrrolidine, piperidine, piperazine, andmorpholine. In another embodiment is a compound of Formula (If), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is C₅₋₉heterocycloalkyl optionallysubstituted with 1 or 2 R¹⁴, wherein the C₅₋₉heterocycloalkyl is abicyclic heterocycloalkyl. In another embodiment is a compound ofFormula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₅₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴, wherein theC₅₋₉heterocycloalkyl is a spirocyclic heterocycloalkyl. In anotherembodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is

In another embodiment is a compound of Formula (If), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₁₋₉heteroaryl optionally substituted with 1or 2 R¹⁴. In another embodiment is a compound of Formula (If), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is an unsubstituted C₁₋₉heteroaryl.In another embodiment is a compound of Formula (If), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (If), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl optionally substituted with 1or 2 R¹⁴, wherein the C₂₋₉heteroaryl is selected from pyrrole, furan,thiophene, thiazole, pyrazole, oxazole, oxadiazole, thiadiazole,pyridine, pyrimidine, pyrazine, indole, benzothiophene, benzofuran, andimidazopyridine. In another embodiment is a compound of Formula (If), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is

In another embodiment is a compound of Formula (If), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is H, CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, orC₁₋₆haloalkoxy. In another embodiment is a compound of Formula (If), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁵ is H. In another embodiment is acompound of Formula (If), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵ is—CN. In another embodiment is a compound of Formula (If), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is halogen. In another embodiment is a compoundof Formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁵ is —Cl. Inanother embodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —F. In another embodiment is a compound ofFormula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (If), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —CH₃. In another embodiment is a compound ofFormula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkyl.In another embodiment is a compound of Formula (If), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —CF₃. In another embodiment is a compound ofFormula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkoxy.In another embodiment is a compound of Formula (If), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —OCF₃.

In another embodiment is a compound of Formula (I) having the structureof Formula (Ig):

wherein:

-   -   R¹ is —N(R²)C(O)R¹⁵ or —N(H)SO₂R¹⁵;    -   R² is H or C₁₋₆alkyl;    -   A is N or C(H);    -   X is —O—, —N(R¹⁶)—, or —CH₂N(R¹⁶)CH₂—;    -   R⁴ is H, halogen, —OR⁷, C₁₋₆alkyl, C₁₋₆alkyl-OH, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, —O—C₃₋₈cycloalkyl,        —O—C₃₋₈cycloalkyl-OH, —N(H)—C₁₋₆alkyl-CO₂H, —SO₂R¹⁷, —CO₂R⁸,        —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl,        wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   R⁵ is H, —CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy,        or phenyl;    -   R⁶ is H, halogen, or C₁₋₆alkyl;    -   R⁷ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl, wherein        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   each R⁸ and each R⁹ are independently selected from H and        C₁₋₆alkyl; or R⁸ and R⁹ together with the nitrogen to which they        are attached are combined to form a heterocycloalkyl ring;    -   R¹² is H, halogen, or C₁₋₆alkyl;    -   R¹³ is H or C₁₋₆alkyl;    -   each R¹⁴ is independently selected from halogen, —OH, oxo,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, —C₁₋₆alkyl-OH,        C₃₋₈cycloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹, —C(O)—C₁₋₆alkyl,        —C(O)—C₁₋₆alkyl-OH, —SO₂—C₁₋₆alkyl, —N(R⁸)SO₂—C₁₋₆alkyl, and        —N(R⁸)C(O)—C₁₋₆alkyl;    -   R¹⁵ is C₁₋₆alkyl or C₃₋₈cycloalkyl;    -   R¹⁶ is H, C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, or —CH₂CO₂H;    -   R¹⁷ is C₁₋₆alkyl or C₃₋₈cycloalkyl; and    -   v is 0 or 1;    -   or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or        pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula (Ib), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, having the structure

In another embodiment is a compound of Formula (Ib), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, having the structure

In another embodiment is a compound of Formula (Ig), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹ is —N(R²)C(O)R¹⁵. In another embodiment is acompound of Formula (Ig), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹ is—N(R²)C(O)R¹⁵ and R² is H. In another embodiment is a compound ofFormula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula (Ig),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Ig), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Ig), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² isC₁₋₆alkyl. In another embodiment is a compound of Formula (Ig), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² is —CH₃. Inanother embodiment is a compound of Formula (Ig), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₁₋₆alkyl. In anotherembodiment is a compound of Formula (Ig), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is —CH₃. In anotherembodiment is a compound of Formula (Ig), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₃₋₈cycloalkyl. Inanother embodiment is a compound of Formula (Ig), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(H)SO₂R¹⁵. In another embodiment is a compoundof Formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵and R¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula(Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Ig), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl.

In another embodiment is a compound of Formula (Ig), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein X is —O—. In another embodiment is a compound ofFormula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein X is —N(R¹⁶)—. Inanother embodiment is a compound of Formula (Ig), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein X is —N(H)—. In another embodiment is a compound ofFormula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein X is —N(CH₃)—. Inanother embodiment is a compound of Formula (Ig), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein X is —CH₂N(R¹⁶)CH₂—. In another embodiment is acompound of Formula (Ig), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein X is—CH₂N(H)CH₂—. In another embodiment is a compound of Formula (Ig), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein X is —CH₂N(CH₃)CH₂—.

In another embodiment is a compound of Formula (Ig), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein A is N. In another embodiment is a compound ofFormula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein A is C(H).

In another embodiment is a compound of Formula (Ig), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein v is 0. In another embodiment is a compound ofFormula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein v is 1.

In another embodiment is a compound of Formula (Ig), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is halogen, —OR⁷, C₁₋₆alkyl-OH,—N(H)—C₁₋₆alkyl-CO₂H, C₂₋₆alkynyl, C₁₋₆haloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl,wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, orC₁₋₉heteroaryl are optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (Ig), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is halogen, —OR⁷, —N(H)—C₁₋₆alkyl-CO₂H,C₁₋₆haloalkyl, —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, orC₁₋₉heteroaryl, wherein C₂₋₉heterocycloalkyl or C₁₋₉heteroaryl areoptionally substituted with 1 or 2 R¹⁴. In another embodiment is acompound of Formula (Ig), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ ishalogen. In another embodiment is a compound of Formula (Ig), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —Cl. In another embodiment is acompound of Formula (Ig), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ isC₁₋₆haloalkyl. In another embodiment is a compound of Formula (Ig), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —CF₃. In another embodiment is acompound of Formula (Ig), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)—C₁₋₆alkyl-CO₂H. In another embodiment is a compound of Formula(Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —N(H)CH₂CO₂H. Inanother embodiment is a compound of Formula (Ig), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —N(H)CH₂CH₂CO₂H. In another embodiment is acompound of Formula (Ig), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)CH₂CH₂CH₂CO₂H. In another embodiment is a compound of Formula (Ig),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —C(O)NR⁸R⁹. Inanother embodiment is a compound of Formula (Ig), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —C(O)NH₂. In another embodiment is a compound ofFormula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is C₃₋₈cycloalkyl.In another embodiment is a compound of Formula (Ig), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is —OR'. In another embodiment is a compound ofFormula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isunsubstituted C₃₋₈cycloalkyl or C₆₋₁₀aryl optionally substituted withhalogen. In another embodiment is a compound of Formula (Ig), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is unsubstitutedC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Ig), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is phenyl optionallysubstituted with halogen. In another embodiment is a compound of Formula(Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with halogen. In another embodiment is a compound ofFormula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with —Cl. In another embodiment is a compound ofFormula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₂₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (Ig), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is an unsubstituted C₂₋₉heterocycloalkyl. In anotherembodiment is a compound of Formula (Ig), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is C₂₋₉heterocycloalkyl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (Ig), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₄₋₅heterocycloalkyl optionally substitutedwith 1 or 2 R¹⁴, wherein the C₄₋₅heterocycloalkyl is a monocyclicheterocycloalkyl selected from pyrrolidine, piperidine, piperazine, andmorpholine. In another embodiment is a compound of Formula (Ig), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is C₅₋₉heterocycloalkyl optionallysubstituted with 1 or 2 R¹⁴, wherein the C₅₋₉heterocycloalkyl is abicyclic heterocycloalkyl. In another embodiment is a compound ofFormula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₅₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴, wherein theC₅₋₉heterocycloalkyl is a spirocyclic heterocycloalkyl. In anotherembodiment is a compound of Formula (Ig), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is

In another embodiment is a compound of Formula (Ig), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₁₋₉heteroaryl optionally substituted with 1or 2 R¹⁴. In another embodiment is a compound of Formula (Ig), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is an unsubstituted C₁₋₉heteroaryl.In another embodiment is a compound of Formula (Ig), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (Ig), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl optionally substituted with 1or 2 R¹⁴, wherein the C₂₋₉heteroaryl is selected from pyrrole, furan,thiophene, thiazole, pyrazole, oxazole, oxadiazole, thiadiazole,pyridine, pyrimidine, pyrazine, indole, benzothiophene, benzofuran, andimidazopyridine. In another embodiment is a compound of Formula (Ig), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is

In another embodiment is a compound of Formula (Ig), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is H, CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, orC₁₋₆haloalkoxy. In another embodiment is a compound of Formula (Ig), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁵ is H. In another embodiment is acompound of Formula (Ig), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵ is—CN. In another embodiment is a compound of Formula (Ig), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is halogen. In another embodiment is a compoundof Formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁵ is —Cl. Inanother embodiment is a compound of Formula (Ig), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —F. In another embodiment is a compound ofFormula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ig), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —CH₃. In another embodiment is a compound ofFormula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkyl.In another embodiment is a compound of Formula (Ig), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —CF₃. In another embodiment is a compound ofFormula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkoxy.In another embodiment is a compound of Formula (Ig), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —OCF₃. In another embodiment is a compoundof Formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁶ is H. In anotherembodiment is a compound of Formula (Ig), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is halogen. In another embodiment is a compound ofFormula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is —Cl. In anotherembodiment is a compound of Formula (Ig), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —F. In another embodiment is a compound ofFormula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ig), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —CH₃.

In another embodiment is a compound of Formula (Ig), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is H. In another embodiment is a compound ofFormula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ig), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃. In another embodiment is a compound ofFormula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹³ is H. In anotherembodiment is a compound of Formula (Ig), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹³ is —CH₃. Inanother embodiment is a compound of Formula (Ig), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is H and R¹³ is H. In another embodiment is acompound of Formula (Ig), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is H and R¹³ is C₁₋₆alkyl. In another embodiment is a compound ofFormula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is H and R¹³ is—CH₃. In another embodiment is a compound of Formula (Ig), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is C₁₋₆alkyl and R¹³ is H. In anotherembodiment is a compound of Formula (Ig), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃ and R¹³ is H. In another embodiment is acompound of Formula (Ig), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is C₁₋₆alkyl and R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹² is —CH₃ and R¹³is —CH₃.

In another embodiment is a compound of Formula (I) having the structureof Formula (Ih):

wherein:

-   -   R¹ is —N(R²)C(O)R¹⁵ or —N(H)SO₂R¹⁵;    -   R² is H or C₁₋₆alkyl;    -   A is N or C(H);    -   X is —O—, —N(R¹⁶)—, or —CH₂N(R¹⁶)CH₂—;    -   R⁴ is H, halogen, —OR⁷, C₁₋₆alkyl, C₁₋₆alkyl-OH, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, —O—C₃₋₈cycloalkyl,        —O—C₃₋₈cycloalkyl-OH, —N(H)—C₁₋₆alkyl-CO₂H, —SO₂R¹⁷, —CO₂R⁸,        —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl,        wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   R⁵ is H, —CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy,        or phenyl; R⁶ is H, halogen, or C₁₋₆alkyl;    -   R⁷ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl, wherein        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R⁴;    -   each R⁸ and each R⁹ are independently selected from H and        C₁₋₆alkyl; or R⁸ and R⁹ together with the nitrogen to which they        are attached are combined to form a heterocycloalkyl ring;    -   each R¹⁴ is independently selected from halogen, —OH, oxo,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, —C₁₋₆alkyl-OH,        C₃₋₈cycloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹, —C(O)—C₁₋₆alkyl,        —C(O)—C₁₋₆alkyl-OH, —SO₂—C₁₋₆alkyl, —N(R⁸)SO₂—C₁₋₆alkyl, and        —N(R⁸)C(O)—C₁₋₆alkyl;    -   R¹⁵ is C₁₋₆alkyl or C₃₋₈cycloalkyl;    -   R¹⁶ is H, C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, or —CH₂CO₂H;    -   R¹⁷ is C₁₋₆alkyl or C₃₋₈cycloalkyl; and    -   v is 0 or 1;    -   or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or        pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula (Ih), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹ is —N(R²)C(O)R¹⁵. In another embodiment is acompound of Formula (Ih), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹ is—N(R²)C(O)R¹⁵ and R² is H. In another embodiment is a compound ofFormula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula (Ih),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Ih), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Ih), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² isC₁₋₆alkyl. In another embodiment is a compound of Formula (Ih), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² is —CH₃. Inanother embodiment is a compound of Formula (Ih), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₁₋₆alkyl. In anotherembodiment is a compound of Formula (Ih), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is —CH₃. In anotherembodiment is a compound of Formula (Ih), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₃₋₈cycloalkyl. Inanother embodiment is a compound of Formula (Ih), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(H)SO₂R¹⁵. In another embodiment is a compoundof Formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵and R¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula(Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Ih), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl.

In another embodiment is a compound of Formula (Ih), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein X is —O—. In another embodiment is a compound ofFormula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein X is —N(R¹⁶)—. Inanother embodiment is a compound of Formula (Ih), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein X is —N(H)—. In another embodiment is a compound ofFormula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein X is —N(CH₃)—. Inanother embodiment is a compound of Formula (Ih), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein X is —CH₂N(R¹⁶)CH₂—. In another embodiment is acompound of Formula (Ih), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein X is—CH₂N(H)CH₂—. In another embodiment is a compound of Formula (Ih), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein X is —CH₂N(CH₃)CH₂—.

In another embodiment is a compound of Formula (Ih), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein A is N. In another embodiment is a compound ofFormula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein A is C(H).

In another embodiment is a compound of Formula (Ih), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein v is 0. In another embodiment is a compound ofFormula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein v is 1.

In another embodiment is a compound of Formula (Ih), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is halogen, —OR⁷, C₁₋₆alkyl-OH,—N(H)—C₁₋₆alkyl-CO₂H, C₂₋₆alkynyl, C₁₋₆haloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl,wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, orC₁₋₉heteroaryl are optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (Ih), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is halogen, —OR⁷, —N(H)—C₁₋₆alkyl-CO₂H,C₁₋₆haloalkyl, —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, orC₁₋₉heteroaryl, wherein C₂₋₉heterocycloalkyl or C₁₋₉heteroaryl areoptionally substituted with 1 or 2 R¹⁴. In another embodiment is acompound of Formula (Ih), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ ishalogen. In another embodiment is a compound of Formula (Ih), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —Cl. In another embodiment is acompound of Formula (Ih), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ isC₁₋₆haloalkyl. In another embodiment is a compound of Formula (Ih), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —CF₃. In another embodiment is acompound of Formula (Ih), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)—C₁₋₆alkyl-CO₂H. In another embodiment is a compound of Formula(Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —N(H)CH₂CO₂H. Inanother embodiment is a compound of Formula (Ih), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —N(H)CH₂CH₂CO₂H. In another embodiment is acompound of Formula (Ih), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)CH₂CH₂CH₂CO₂H. In another embodiment is a compound of Formula (Ih),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —C(O)NR⁸R⁹. Inanother embodiment is a compound of Formula (Ih), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —C(O)NH₂. In another embodiment is a compound ofFormula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is C₃₋₈cycloalkyl.In another embodiment is a compound of Formula (Ih), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is —OR⁷. In another embodiment is a compound ofFormula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isunsubstituted C₃₋₈cycloalkyl or C₆₋₁₀aryl optionally substituted withhalogen. In another embodiment is a compound of Formula (Ih), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is unsubstitutedC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Ih), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is phenyl optionallysubstituted with halogen. In another embodiment is a compound of Formula(Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with halogen. In another embodiment is a compound ofFormula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with —Cl. In another embodiment is a compound ofFormula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₂₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (Ih), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is an unsubstituted C₂₋₉heterocycloalkyl. In anotherembodiment is a compound of Formula (Ih), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is C₂₋₉heterocycloalkyl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (Ih), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₄₋₅heterocycloalkyl optionally substitutedwith 1 or 2 R¹⁴, wherein the C₄₋₅heterocycloalkyl is a monocyclicheterocycloalkyl selected from pyrrolidine, piperidine, piperazine, andmorpholine. In another embodiment is a compound of Formula (Ih), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is C₅₋₉heterocycloalkyl optionallysubstituted with 1 or 2 R¹⁴, wherein the C₅₋₉heterocycloalkyl is abicyclic heterocycloalkyl. In another embodiment is a compound ofFormula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₅₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴, wherein theC₅₋₉heterocycloalkyl is a spirocyclic heterocycloalkyl. In anotherembodiment is a compound of Formula (Ih), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is

In another embodiment is a compound of Formula (Ih), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₁₋₉heteroaryl optionally substituted with 1or 2 R¹⁴. In another embodiment is a compound of Formula (Ih), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is an unsubstituted C₁₋₉heteroaryl.In another embodiment is a compound of Formula (Ih), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (Ih), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl optionally substituted with 1or 2 R¹⁴, wherein the C₂₋₉heteroaryl is selected from pyrrole, furan,thiophene, thiazole, pyrazole, oxazole, oxadiazole, thiadiazole,pyridine, pyrimidine, pyrazine, indole, benzothiophene, benzofuran, andimidazopyridine. In another embodiment is a compound of Formula (Ih), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is

In another embodiment is a compound of Formula (Ih), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is H, CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, orC₁₋₆haloalkoxy. In another embodiment is a compound of Formula (Ih), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁵ is H. In another embodiment is acompound of Formula (Ih), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵ is—CN. In another embodiment is a compound of Formula (Ih), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is halogen. In another embodiment is a compoundof Formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁵ is —Cl. Inanother embodiment is a compound of Formula (Ih), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —F. In another embodiment is a compound ofFormula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ih), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —CH₃. In another embodiment is a compound ofFormula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkyl.In another embodiment is a compound of Formula (Ih), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —CF₃. In another embodiment is a compound ofFormula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkoxy.In another embodiment is a compound of Formula (Ih), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —OCF₃. In another embodiment is a compoundof Formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁶ is H. In anotherembodiment is a compound of Formula (Ih), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is halogen. In another embodiment is a compound ofFormula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is —Cl. In anotherembodiment is a compound of Formula (Ih), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —F. In another embodiment is a compound ofFormula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ih), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —CH₃.

In another embodiment is a compound of Formula (I) having the structureof Formula (Ii):

wherein:

-   -   R¹ is —N(R²)C(O)R¹⁵ or —N(H)SO₂R¹⁵;    -   R² is H or C₁₋₆alkyl;    -   R⁴ is H, halogen, —OR⁷, C₁₋₆alkyl, C₁₋₆alkyl-OH, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, —O—C₃₋₈cycloalkyl,        —O—C₃₋₈cycloalkyl-OH, —N(H)—C₁₋₆alkyl-CO₂H, —SO₂R¹⁷, —CO₂R⁸,        —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl,        wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   R⁵ is H, —CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy,        or phenyl;    -   R⁶ is H, halogen, or C₁₋₆alkyl;    -   R⁷ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl, wherein        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   each R⁸ and each R⁹ are independently selected from H and        C₁₋₆alkyl; or R⁸ and R⁹ together with the nitrogen to which they        are attached are combined to form a heterocycloalkyl ring;    -   each R¹⁴ is independently selected from halogen, —OH, oxo,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, —C₁₋₆alkyl-OH,        C₃₋₈cycloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹, —C(O)—C₁₋₆alkyl,        —C(O)—C₁₋₆alkyl-OH, —SO₂—C₁₋₆alkyl, —N(R⁸)SO₂—C₁₋₆alkyl, and        —N(R⁸)C(O)—C₁₋₆alkyl;    -   R¹⁵ is C₁₋₆alkyl or C₃₋₈cycloalkyl; and    -   R¹⁷ is C₁₋₆alkyl or C₃₋₈cycloalkyl;    -   or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or        pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula (Ii), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹ is —N(R²)C(O)R¹⁵. In another embodiment is acompound of Formula (Ii), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹ is—N(R²)C(O)R¹⁵ and R² is H. In another embodiment is a compound ofFormula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula (Ii),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Ii), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Ii), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² isC₁₋₆alkyl. In another embodiment is a compound of Formula (Ii), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² is —CH₃. Inanother embodiment is a compound of Formula (Ii), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₁₋₆alkyl. In anotherembodiment is a compound of Formula (Ii), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is —CH₃. In anotherembodiment is a compound of Formula (Ii), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₃₋₈cycloalkyl. Inanother embodiment is a compound of Formula (Ii), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(H)SO₂R¹⁵. In another embodiment is a compoundof Formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵and R¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula(Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Ii), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl.

In another embodiment is a compound of Formula (Ii), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is halogen, —OR⁷, C₁₋₆alkyl-OH,—N(H)—C₁₋₆alkyl-CO₂H, C₂₋₆alkynyl, C₁₋₆haloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl,wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, orC₁₋₉heteroaryl are optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (Ii), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is halogen, —OR⁷, —N(H)—C₁₋₆alkyl-CO₂H,C₁₋₆haloalkyl, —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, orC₁₋₉heteroaryl, wherein C₂₋₉heterocycloalkyl or C₁₋₉heteroaryl areoptionally substituted with 1 or 2 R¹⁴. In another embodiment is acompound of Formula (Ii), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ ishalogen. In another embodiment is a compound of Formula (Ii), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —Cl. In another embodiment is acompound of Formula (Ii), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ isC₁₋₆haloalkyl. In another embodiment is a compound of Formula (Ii), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —CF₃. In another embodiment is acompound of Formula (Ii), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)—C₁₋₆alkyl-CO₂H. In another embodiment is a compound of Formula(Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —N(H)CH₂CO₂H. Inanother embodiment is a compound of Formula (Ii), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —N(H)CH₂CH₂CO₂H. In another embodiment is acompound of Formula (Ii), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)CH₂CH₂CH₂CO₂H. In another embodiment is a compound of Formula (Ii),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —C(O)NR⁸R⁹. Inanother embodiment is a compound of Formula (Ii), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —C(O)NH₂. In another embodiment is a compound ofFormula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is C₃₋₈cycloalkyl.In another embodiment is a compound of Formula (Ii), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is —OR'. In another embodiment is a compound ofFormula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isunsubstituted C₃₋₈cycloalkyl or C₆₋₁₀aryl optionally substituted withhalogen. In another embodiment is a compound of Formula (Ii), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is unsubstitutedC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Ii), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is phenyl optionallysubstituted with halogen. In another embodiment is a compound of Formula(Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with halogen. In another embodiment is a compound ofFormula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with —Cl. In another embodiment is a compound ofFormula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₂₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (Ii), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is an unsubstituted C₂₋₉heterocycloalkyl. In anotherembodiment is a compound of Formula (Ii), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is C₂₋₉heterocycloalkyl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (Ii), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₄₋₅heterocycloalkyl optionally substitutedwith 1 or 2 R¹⁴, wherein the C₄₋₅heterocycloalkyl is a monocyclicheterocycloalkyl selected from pyrrolidine, piperidine, piperazine, andmorpholine. In another embodiment is a compound of Formula (Ii), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is C₅₋₉heterocycloalkyl optionallysubstituted with 1 or 2 R¹⁴, wherein the C₅₋₉heterocycloalkyl is abicyclic heterocycloalkyl. In another embodiment is a compound ofFormula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₅₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴, wherein theC₅₋₉heterocycloalkyl is a spirocyclic heterocycloalkyl. In anotherembodiment is a compound of Formula (Ii), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is

In another embodiment is a compound of Formula (Ii), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₁₋₉heteroaryl optionally substituted with 1or 2 R¹⁴. In another embodiment is a compound of Formula (Ii), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is an unsubstituted C₁₋₉heteroaryl.In another embodiment is a compound of Formula (Ii), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (Ii), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl optionally substituted with 1or 2 R¹⁴, wherein the C₂₋₉heteroaryl is selected from pyrrole, furan,thiophene, thiazole, pyrazole, oxazole, oxadiazole, thiadiazole,pyridine, pyrimidine, pyrazine, indole, benzothiophene, benzofuran, andimidazopyridine. In another embodiment is a compound of Formula (Ii), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is

In another embodiment is a compound of Formula (Ii), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is H, CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, orC₁₋₆haloalkoxy. In another embodiment is a compound of Formula (Ii), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁵ is H. In another embodiment is acompound of Formula (Ii), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵ is—CN. In another embodiment is a compound of Formula (Ii), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is halogen. In another embodiment is a compoundof Formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁵ is —Cl. Inanother embodiment is a compound of Formula (Ii), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —F. In another embodiment is a compound ofFormula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ii), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —CH₃. In another embodiment is a compound ofFormula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkyl.In another embodiment is a compound of Formula (Ii), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —CF₃. In another embodiment is a compound ofFormula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkoxy.In another embodiment is a compound of Formula (Ii), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —OCF₃. In another embodiment is a compoundof Formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁶ is H. In anotherembodiment is a compound of Formula (Ii), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is halogen. In another embodiment is a compound ofFormula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is —Cl. In anotherembodiment is a compound of Formula (Ii), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —F. In another embodiment is a compound ofFormula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ii), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —CH₃.

In another embodiment is a compound of Formula (I) having the structureof Formula (Ij):

wherein:

-   -   R¹ is —N(R²)C(O)R¹⁵ or —N(H)SO₂R¹⁵;    -   R² is H or C₁₋₆alkyl;    -   R⁴ is H, halogen, —OR⁷, C₁₋₆alkyl, C₁₋₆alkyl-OH, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, —O—C₃₋₈cycloalkyl,        —O—C₃₋₈cycloalkyl-OH, —N(H)—C₁₋₆alkyl-CO₂H, —SO₂R¹⁷, —CO₂R⁸,        —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl,        wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   R⁵ is H, —CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy,        or phenyl;    -   R⁶ is H, halogen, or C₁₋₆alkyl;    -   R⁷ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl, wherein        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   each R⁸ and each R⁹ are independently selected from H and        C₁₋₆alkyl; or R⁸ and R⁹ together with the nitrogen to which they        are attached are combined to form a heterocycloalkyl ring;    -   R¹² is H, halogen, or C₁₋₆alkyl;    -   R¹³ is H or C₁₋₆alkyl;    -   each R¹⁴ is independently selected from halogen, —OH, oxo,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, —C₁₋₆alkyl-OH,        C₃₋₈cycloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹, —C(O)—C₁₋₆alkyl,        —C(O)—C₁₋₆alkyl-OH, —SO₂—C₁₋₆alkyl, —N(R⁸)SO₂—C₁₋₆alkyl, and        —N(R⁸)C(O)—C₁₋₆alkyl;    -   R¹⁵ is C₁₋₆alkyl or C₃₋₈cycloalkyl; and    -   R¹⁷ is C₁₋₆alkyl or C₃₋₈cycloalkyl;    -   or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or        pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula (Ij), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹ is —N(R²)C(O)R¹⁵. In another embodiment is acompound of Formula (Ij), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹ is—N(R²)C(O)R¹⁵ and R² is H. In another embodiment is a compound ofFormula (Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula (Ij),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Ij), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Ij), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² isC₁₋₆alkyl. In another embodiment is a compound of Formula (Ij), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² is —CH₃. Inanother embodiment is a compound of Formula (Ij), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₁₋₆alkyl. In anotherembodiment is a compound of Formula (Ij), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is —CH₃. In anotherembodiment is a compound of Formula (Ij), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₃₋₈cycloalkyl. Inanother embodiment is a compound of Formula (Ij), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(H)SO₂R¹⁵. In another embodiment is a compoundof Formula (Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵and R¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula(Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Ij), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl.

In another embodiment is a compound of Formula (Ij), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is halogen, —OR⁷, C₁₋₆alkyl-OH,—N(H)—C₁₋₆alkyl-CO₂H, C₂₋₆alkynyl, C₁₋₆haloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl,wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, orC₁₋₉heteroaryl are optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (Ij), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is halogen, —OR⁷, —N(H)—C₁₋₆alkyl-CO₂H,C₁₋₆haloalkyl, —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, orC₁₋₉heteroaryl, wherein C₂₋₉heterocycloalkyl or C₁₋₉heteroaryl areoptionally substituted with 1 or 2 R¹⁴. In another embodiment is acompound of Formula (Ij), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ ishalogen. In another embodiment is a compound of Formula (Ij), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —Cl. In another embodiment is acompound of Formula (Ij), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ isC₁₋₆haloalkyl. In another embodiment is a compound of Formula (Ij), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —CF₃. In another embodiment is acompound of Formula (Ij), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)—C₁₋₆alkyl-CO₂H. In another embodiment is a compound of Formula(Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —N(H)CH₂CO₂H. Inanother embodiment is a compound of Formula (Ij), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —N(H)CH₂CH₂CO₂H. In another embodiment is acompound of Formula (Ij), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)CH₂CH₂CH₂CO₂H. In another embodiment is a compound of Formula (Ij),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —C(O)NR⁸R⁹. Inanother embodiment is a compound of Formula (Ij), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —C(O)NH₂. In another embodiment is a compound ofFormula (Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is C₃₋₈cycloalkyl.In another embodiment is a compound of Formula (Ij), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is —OR⁷. In another embodiment is a compound ofFormula (Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isunsubstituted C₃₋₈cycloalkyl or C₆₋₁₀aryl optionally substituted withhalogen. In another embodiment is a compound of Formula (Ij), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is unsubstitutedC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Ij), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is phenyl optionallysubstituted with halogen. In another embodiment is a compound of Formula(Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with halogen. In another embodiment is a compound ofFormula (Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with —Cl. In another embodiment is a compound ofFormula (Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₂₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (Ij), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is an unsubstituted C₂₋₉heterocycloalkyl. In anotherembodiment is a compound of Formula (Ij), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is C₂₋₉heterocycloalkyl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (Ij), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₄₋₅heterocycloalkyl optionally substitutedwith 1 or 2 R¹⁴, wherein the C₄₋₅heterocycloalkyl is a monocyclicheterocycloalkyl selected from pyrrolidine, piperidine, piperazine, andmorpholine. In another embodiment is a compound of Formula (Ij), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is C₅₋₉heterocycloalkyl optionallysubstituted with 1 or 2 R¹⁴, wherein the C₅₋₉heterocycloalkyl is abicyclic heterocycloalkyl. In another embodiment is a compound ofFormula (Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₅₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴, wherein theC₅₋₉heterocycloalkyl is a spirocyclic heterocycloalkyl. In anotherembodiment is a compound of Formula (Ij), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is

In another embodiment is a compound of Formula (Ij), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₁₋₉heteroaryl optionally substituted with 1or 2 R¹⁴. In another embodiment is a compound of Formula (Ij), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is an unsubstituted C₁₋₉heteroaryl.In another embodiment is a compound of Formula (Ij), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (Ij), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl optionally substituted with 1or 2 R¹⁴, wherein the C₂₋₉heteroaryl is selected from pyrrole, furan,thiophene, thiazole, pyrazole, oxazole, oxadiazole, thiadiazole,pyridine, pyrimidine, pyrazine, indole, benzothiophene, benzofuran, andimidazopyridine. In another embodiment is a compound of Formula (Ij), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is

In another embodiment is a compound of Formula (Ij), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is H, CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, orC₁₋₆haloalkoxy. In another embodiment is a compound of Formula (Ij), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁵ is H. In another embodiment is acompound of Formula (Ij), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵ is—CN. In another embodiment is a compound of Formula (Ij), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is halogen. In another embodiment is a compoundof Formula (Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁵ is —Cl. Inanother embodiment is a compound of Formula (Ij), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —F. In another embodiment is a compound ofFormula (Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ij), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —CH₃. In another embodiment is a compound ofFormula (Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkyl.In another embodiment is a compound of Formula (Ij), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —CF₃. In another embodiment is a compound ofFormula (Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkoxy.In another embodiment is a compound of Formula (Ij), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —OCF₃. In another embodiment is a compoundof Formula (Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁶ is H. In anotherembodiment is a compound of Formula (Ij), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is halogen. In another embodiment is a compound ofFormula (Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is —Cl. In anotherembodiment is a compound of Formula (Ij), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —F. In another embodiment is a compound ofFormula (Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ij), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —CH₃.

In another embodiment is a compound of Formula (Ij), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is H. In another embodiment is a compound ofFormula (Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ij), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃. In another embodiment is a compound ofFormula (Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹³ is H. In anotherembodiment is a compound of Formula (Ij), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹³ is —CH₃. Inanother embodiment is a compound of Formula (Ij), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is H and R¹³ is H. In another embodiment is acompound of Formula (Ij), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is H and R¹³ is C₁₋₆alkyl. In another embodiment is a compound ofFormula (Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is H and R¹³ is—CH₃. In another embodiment is a compound of Formula (Ij), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is C₁₋₆alkyl and R¹³ is H. In anotherembodiment is a compound of Formula (Ij), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃ and R¹³ is H. In another embodiment is acompound of Formula (Ij), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is C₁₋₆alkyl and R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (Ij), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹² is —CH₃ and R¹³is —CH₃.

In another embodiment is a compound of Formula (I) having the structureof Formula (Ik):

wherein:

-   -   R¹ is —N(R²)C(O)R¹⁵ or —N(H)SO₂R¹⁵;    -   R² is H or C₁₋₆alkyl;    -   R⁴ is H, halogen, —OR⁷, C₁₋₆alkyl, C₁₋₆alkyl-OH, C₂₋₆ alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, —O—C₃₋₈cycloalkyl,        —O—C₃₋₈cycloalkyl-OH, —N(H)—C₁₋₆alkyl-CO₂H, —SO₂R¹⁷,—CO₂R⁸,        —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl,        wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   R⁵ is H, —CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy,        or phenyl;    -   R⁶ is H, halogen, or C₁₋₆alkyl;    -   R⁷ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl, wherein        C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl are        optionally substituted with 1 or 2 R¹⁴;    -   each R⁸ and each R⁹ are independently selected from H and        C₁₋₆alkyl; or R⁸ and R⁹ together with the nitrogen to which they        are attached are combined to form a heterocycloalkyl ring;    -   each R¹⁴ is independently selected from halogen, —OH, oxo,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, —C₁₋₆alkyl-OH,        C₃₋₈cycloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹, —C(O)—C₁₋₆alkyl,        —C(O)—C₁₋₆alkyl-OH, —SO₂—C₁₋₆alkyl, —N(R⁸)SO₂—C₁₋₆alkyl, and        —N(R⁸)C(O)—C₁₋₆alkyl;    -   R¹⁵ is C₁₋₆alkyl or C₃₋₈cycloalkyl;    -   R¹⁷ is C₁₋₆alkyl or C₃₋₈cycloalkyl; and    -   R¹⁸ and R¹⁹ are independently selected from H and C₁₋₆alkyl,        wherein R¹⁸ and R¹⁹ are not both H;    -   or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or        pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula (Ik), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹ is —N(R²)C(O)R¹⁵. In another embodiment is acompound of Formula (Ik), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹ is—N(R²)C(O)R¹⁵ and R² is H. In another embodiment is a compound ofFormula (Ik), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula (Ik),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Ik), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Ik), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² isC₁₋₆alkyl. In another embodiment is a compound of Formula (Ik), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² is —CH₃. Inanother embodiment is a compound of Formula (Ik), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₁₋₆alkyl. In anotherembodiment is a compound of Formula (Ik), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is —CH₃. In anotherembodiment is a compound of Formula (Ik), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₃₋₈cycloalkyl. Inanother embodiment is a compound of Formula (Ik), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(H)SO₂R¹⁵. In another embodiment is a compoundof Formula (Ik), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵and R¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula(Ik), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Ik), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl.

In another embodiment is a compound of Formula (Ik), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is halogen, —OR⁷, C₁₋₆alkyl-OH,—N(H)—C₁₋₆alkyl-CO₂H, C₂₋₆alkynyl, C₁₋₆haloalkyl, —CO₂R⁸, —C(O)NR⁸R⁹,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl,wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, orC₁₋₉heteroaryl are optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (Ik), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is halogen, —OR⁷, —N(H)—C₁₋₆alkyl-CO₂H,C₁₋₆haloalkyl, —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, orC₁₋₉heteroaryl, wherein C₂₋₉heterocycloalkyl or C₁₋₉heteroaryl areoptionally substituted with 1 or 2 R¹⁴. In another embodiment is acompound of Formula (Ik), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ ishalogen. In another embodiment is a compound of Formula (Ik), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —Cl. In another embodiment is acompound of Formula (Ik), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ isC₁₋₆haloalkyl. In another embodiment is a compound of Formula (Ik), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —CF₃. In another embodiment is acompound of Formula (Ik), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)—C₁₋₆alkyl-CO₂H. In another embodiment is a compound of Formula(Ik), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —N(H)CH₂CO₂H. Inanother embodiment is a compound of Formula (Ik), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —N(H)CH₂CH₂CO₂H. In another embodiment is acompound of Formula (Ik), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)CH₂CH₂CH₂CO₂H. In another embodiment is a compound of Formula (Ik),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —C(O)NR⁸R⁹. Inanother embodiment is a compound of Formula (Ik), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —C(O)NH₂. In another embodiment is a compound ofFormula (Ik), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is C₃₋₈cycloalkyl.In another embodiment is a compound of Formula (Ik), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is —OR⁷. In another embodiment is a compound ofFormula (Ik), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isunsubstituted C₃₋₈cycloalkyl or C₆₋₁₀aryl optionally substituted withhalogen. In another embodiment is a compound of Formula (Ik), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is unsubstitutedC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Ik), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ is phenyl optionallysubstituted with halogen. In another embodiment is a compound of Formula(Ik), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with halogen. In another embodiment is a compound ofFormula (Ik), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is —OR⁷ and R⁷ isphenyl substituted with —Cl. In another embodiment is a compound ofFormula (Ik), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₂₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴. In anotherembodiment is a compound of Formula (Ik), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is an unsubstituted C₂₋₉heterocycloalkyl. In anotherembodiment is a compound of Formula (Ik), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is C₂₋₉heterocycloalkyl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (Ik), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₄₋₅heterocycloalkyl optionally substitutedwith 1 or 2 R¹⁴, wherein the C₄₋₅heterocycloalkyl is a monocyclicheterocycloalkyl selected from pyrrolidine, piperidine, piperazine, andmorpholine. In another embodiment is a compound of Formula (Ik), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is C₅₋₉heterocycloalkyl optionallysubstituted with 1 or 2 R¹⁴, wherein the C₅₋₉heterocycloalkyl is abicyclic heterocycloalkyl. In another embodiment is a compound ofFormula (Ik), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₅₋₉heterocycloalkyl optionally substituted with 1 or 2 R¹⁴, wherein theC₅₋₉heterocycloalkyl is a spirocyclic heterocycloalkyl. In anotherembodiment is a compound of Formula (Ik), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is

In another embodiment is a compound of Formula (Ik), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₁₋₉heteroaryl optionally substituted with 1or 2 R¹⁴. In another embodiment is a compound of Formula (Ik), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is an unsubstituted C₁₋₉heteroaryl.In another embodiment is a compound of Formula (Ik), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl substituted with 1 or 2 R¹⁴.In another embodiment is a compound of Formula (Ik), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is C₂₋₉heteroaryl optionally substituted with 1or 2 R¹⁴, wherein the C₂₋₉heteroaryl is selected from pyrrole, furan,thiophene, thiazole, pyrazole, oxazole, oxadiazole, thiadiazole,pyridine, pyrimidine, pyrazine, indole, benzothiophene, benzofuran, andimidazopyridine. In another embodiment is a compound of Formula (Ik), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is

In another embodiment is a compound of Formula (Ik), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is H, CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, orC₁₋₆haloalkoxy. In another embodiment is a compound of Formula (Ik), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁵ is H. In another embodiment is acompound of Formula (Ik), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵ is—CN. In another embodiment is a compound of Formula (Ik), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is halogen. In another embodiment is a compoundof Formula (Ik), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁵ is —Cl. Inanother embodiment is a compound of Formula (Ik), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —F. In another embodiment is a compound ofFormula (Ik), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ik), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —CH₃. In another embodiment is a compound ofFormula (Ik), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkyl.In another embodiment is a compound of Formula (Ik), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —CF₃. In another embodiment is a compound ofFormula (Ik), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkoxy.In another embodiment is a compound of Formula (Ik), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —OCF₃. In another embodiment is a compoundof Formula (Ik), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁶ is H. In anotherembodiment is a compound of Formula (Ik), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is halogen. In another embodiment is a compound ofFormula (Ik), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is —Cl. In anotherembodiment is a compound of Formula (Ik), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —F. In another embodiment is a compound ofFormula (Ik), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Ik), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —CH₃.

In another embodiment is a compound of Formula (Ik), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹⁸ is C₁₋₆alkyl. In another embodiment is acompound of Formula (Ik), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁸is C₁₋₆alkyl and R¹⁹ is H. In another embodiment is a compound ofFormula (Ik), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁸ is —CH₃ and R¹⁹ isH. In another embodiment is a compound of Formula (Ik), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹⁹ is C₁₋₆alkyl. In another embodiment is acompound of Formula (Ik), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁸is H and R¹⁹ is C₁₋₆alkyl. In another embodiment is a compound ofFormula (Ik), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁸ is H and R¹⁹ is—CH₃. In another embodiment is a compound of Formula (Ik), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹⁸ and R¹⁹ are C₁₋₆alkyl. In another embodimentis a compound of Formula (Ik), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁸and R¹⁹ are —CH₃.

In another embodiment is a compound of Formula (I) having the structureof Formula (Il):

wherein:

-   -   R¹ is —N(R²)C(O)R¹⁵ or —N(H)SO₂R¹⁵;    -   R² is H or C₁₋₆alkyl;    -   R⁵ is H, —CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy,        or phenyl;    -   R⁶ is H, halogen, or C₁₋₆alkyl;    -   R¹⁰ is —O—C₁₋₆haloalkyl, —O—C₁₋₆alkyl-CO₂H, —O—C₃₋₈cycloalkyl,        —O—C₃₋₈cycloalkyl-CO₂H, —N(H)—C₁₋₆alkyl-CO₂H, or —SO₂R¹⁷;    -   R¹² is H, halogen, or C₁₋₆alkyl;    -   R¹³ is H or C₁₋₆alkyl;    -   R¹⁵ is C₁₋₆alkyl or C₃₋₈cycloalkyl; and    -   R¹⁷ is C₁₋₆alkyl or C₃₋₈cycloalkyl;    -   or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or        pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula (Il), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹ is —N(R²)C(O)R¹⁵. In another embodiment is acompound of Formula (Il), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹ is—N(R²)C(O)R¹⁵ and R² is H. In another embodiment is a compound ofFormula (Il), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula (Il),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Il), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Il), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² isC₁₋₆alkyl. In another embodiment is a compound of Formula (Il), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² is —CH₃. Inanother embodiment is a compound of Formula (Il), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₁₋₆alkyl. In anotherembodiment is a compound of Formula (Il), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is —CH₃. In anotherembodiment is a compound of Formula (Il), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₃₋₈cycloalkyl. Inanother embodiment is a compound of Formula (Il), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(H)SO₂R¹⁵. In another embodiment is a compoundof Formula (Il), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵and R¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula(I1), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Il), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl.

In another embodiment is a compound of Formula (Il), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹⁰ is —O—C₁₋₆alkyl-CO₂H. In another embodiment isa compound of Formula (Il), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁰is —OCH₂CO₂H. In another embodiment is a compound of Formula (Il), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹⁰ is —OCH₂CH₂CO₂H. In anotherembodiment is a compound of Formula (Il), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹⁰ is —OCH₂CH₂CH₂CO₂H. In another embodiment is acompound of Formula (Il), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁰is —N(H)—C₁₋₆alkyl-CO₂H. In another embodiment is a compound of Formula(Il), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁰ is —N(H)CH₂CO₂H.In another embodiment is a compound of Formula (Il), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹⁰ is —N(H)CH₂CH₂CO₂H. In another embodiment is acompound of Formula (Il), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁰is —N(H)CH₂CH₂CH₂CO₂H. In another embodiment is a compound of Formula(Il), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁰ is—O—C₁₋₆haloalkyl. In another embodiment is a compound of Formula (Il),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁰ is —OCF₃. Inanother embodiment is a compound of Formula (Il), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹⁰ is —O—C₃₋₈cycloalkyl. In another embodiment is acompound of Formula (Il), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁰is —O—C₃₋₈cycloalkyl-CO₂H. In another embodiment is a compound ofFormula (Il), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁰ is —SO₂R¹⁷. Inanother embodiment is a compound of Formula (Il), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹⁰ is —SO₂R¹⁷ and R¹⁷ is C₁₋₆alkyl. In anotherembodiment is a compound of Formula (Il), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹⁰ is —SO₂R¹⁷ and R¹⁷ is —CH₃. In another embodimentis a compound of Formula (Il), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁰is —SO₂R¹⁷ and R¹⁷ is C₃₋₈cycloalkyl. In another embodiment is acompound of Formula (Il), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵ isH, CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆haloalkoxy. In anotherembodiment is a compound of Formula (Il), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is H. In another embodiment is a compound of Formula(Il), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is —CN. In anotherembodiment is a compound of Formula (Il), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is halogen. In another embodiment is a compound ofFormula (Il), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is —Cl. In anotherembodiment is a compound of Formula (Il), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —F. In another embodiment is a compound ofFormula (Il), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Il), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —CH₃. In another embodiment is a compound ofFormula (Il), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkyl.In another embodiment is a compound of Formula (Il), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —CF₃. In another embodiment is a compound ofFormula (Il), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkoxy.In another embodiment is a compound of Formula (Il), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —OCF₃. In another embodiment is a compoundof Formula (Il), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁶ is H. In anotherembodiment is a compound of Formula (Il), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is halogen. In another embodiment is a compound ofFormula (Il), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is —Cl. In anotherembodiment is a compound of Formula (Il), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —F. In another embodiment is a compound ofFormula (Il), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Il), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —CH₃.

In another embodiment is a compound of Formula (Il), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is H. In another embodiment is a compound ofFormula (Il), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Il), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃. In another embodiment is a compound ofFormula (Il), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹³ is H. In anotherembodiment is a compound of Formula (Il), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (Il), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹³ is —CH₃. Inanother embodiment is a compound of Formula (Il), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is H and R¹³ is H. In another embodiment is acompound of Formula (Il), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is H and R¹³ is C₁₋₆alkyl. In another embodiment is a compound ofFormula (Il), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is H and R¹³ is—CH₃. In another embodiment is a compound of Formula (Il), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is C₁₋₆alkyl and R¹³ is H. In anotherembodiment is a compound of Formula (Il), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃ and R¹³ is H. In another embodiment is acompound of Formula (Il), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is C₁₋₆alkyl and R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (I1), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹² is —CH₃ and R¹³is —CH₃.

In another embodiment is a compound of Formula (I) having the structureof Formula (Im):

wherein:

-   -   R¹ is —N(R²)C(O)R¹⁵ or —N(H)SO₂R¹⁵;    -   R² is H or C₁₋₆alkyl;    -   R⁵ is H, —CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkoxy, or phenyl;    -   R⁶ is H, halogen, or C₁₋₆alkyl;    -   R¹⁰ is —O—C₁₋₆haloalkyl, —O—C₁₋₆alkyl-CO₂H, —O—C₃₋₈cycloalkyl,        —O—C₃₋₈cycloalkyl-CO₂H, —N(H)—C₁₋₆alkyl-CO₂H, or —SO₂R¹⁷;    -   R¹² is H, halogen, or C₁₋₆alkyl;    -   R¹³ is H or C₁₋₆alkyl;    -   R¹⁵ is C₁₋₆alkyl or C₃₋₈cycloalkyl; and    -   R¹⁷ is C₁₋₆alkyl or C₃₋₈cycloalkyl;    -   or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or        pharmaceutically acceptable salt thereof.

In another embodiment is a compound of Formula (Im), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹ is —N(R²)C(O)R¹⁵. In another embodiment is acompound of Formula (Im), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹ is—N(R²)C(O)R¹⁵ and R² is H. In another embodiment is a compound ofFormula (Im), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula (Im),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Im), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)C(O)R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl. In another embodiment is a compound of Formula (Im), ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² isC₁₋₆alkyl. In another embodiment is a compound of Formula (Im), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(R²)C(O)R¹⁵ and R² is —CH₃. Inanother embodiment is a compound of Formula (Im), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₁₋₆alkyl. In anotherembodiment is a compound of Formula (Im), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is —CH₃. In anotherembodiment is a compound of Formula (Im), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(CH₃)C(O)R¹⁵ and R¹⁵ is C₃₋₈cycloalkyl. Inanother embodiment is a compound of Formula (Im), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(H)SO₂R¹⁵. In another embodiment is a compoundof Formula (Im), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵and R¹⁵ is C₁₋₆alkyl. In another embodiment is a compound of Formula(Im), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ andR¹⁵ is —CH₃. In another embodiment is a compound of Formula (Im), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵ and R¹⁵ isC₃₋₈cycloalkyl.

In another embodiment is a compound of Formula (Im), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹⁰ is —O—C₁₋₆alkyl-CO₂H. In another embodiment isa compound of Formula (Im), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁰is —OCH₂CO₂H. In another embodiment is a compound of Formula (Im), or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹⁰ is —OCH₂CH₂CO₂H. In anotherembodiment is a compound of Formula (Im), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹⁰ is —OCH₂CH₂CH₂CO₂H. In another embodiment is acompound of Formula (Im), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁰is —N(H)—C₁₋₆alkyl-CO₂H. In another embodiment is a compound of Formula(Im), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁰ is —N(H)CH₂CO₂H.In another embodiment is a compound of Formula (Im), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹⁰ is —N(H)CH₂CH₂CO₂H. In another embodiment is acompound of Formula (Im), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁰is —N(H)CH₂CH₂CH₂CO₂H. In another embodiment is a compound of Formula(Im), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁰ is—O—C₁₋₆haloalkyl. In another embodiment is a compound of Formula (Im),or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁰ is —OCF₃. Inanother embodiment is a compound of Formula (Im), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹⁰ is —O—C₃₋₈cycloalkyl. In another embodiment is acompound of Formula (Im), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁰is —O—C₃₋₈cycloalkyl-CO₂H. In another embodiment is a compound ofFormula (Im), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁰ is —SO₂R¹⁷. Inanother embodiment is a compound of Formula (Im), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹⁰ is —SO₂R¹⁷ and R¹⁷ is C₁₋₆alkyl. In anotherembodiment is a compound of Formula (Im), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹⁰ is —SO₂R¹⁷ and R¹⁷ is —CH₃. In another embodimentis a compound of Formula (Im), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁰is —SO₂R¹⁷ and R¹⁷ is C₃₋₈cycloalkyl. In another embodiment is acompound of Formula (Im), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵ isH, CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆haloalkoxy. In anotherembodiment is a compound of Formula (Im), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is H. In another embodiment is a compound of Formula(Im), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is —CN. In anotherembodiment is a compound of Formula (Im), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is halogen. In another embodiment is a compound ofFormula (Im), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is —Cl. In anotherembodiment is a compound of Formula (Im), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —F. In another embodiment is a compound ofFormula (Im), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Im), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is —CH₃. In another embodiment is a compound ofFormula (Im), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkyl.In another embodiment is a compound of Formula (Im), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —CF₃. In another embodiment is a compound ofFormula (Im), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkoxy.In another embodiment is a compound of Formula (Im), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is —OCF₃. In another embodiment is a compoundof Formula (Im), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁶ is H. In anotherembodiment is a compound of Formula (Im), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is halogen. In another embodiment is a compound ofFormula (Im), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is —Cl. In anotherembodiment is a compound of Formula (Im), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —F. In another embodiment is a compound ofFormula (Im), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Im), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is —CH₃.

In another embodiment is a compound of Formula (Im), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is H. In another embodiment is a compound ofFormula (Im), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is C₁₋₆alkyl. Inanother embodiment is a compound of Formula (Im), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃. In another embodiment is a compound ofFormula (Im), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹³ is H. In anotherembodiment is a compound of Formula (Im), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (Im), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹³ is —CH₃. Inanother embodiment is a compound of Formula (Im), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is H and R¹³ is H. In another embodiment is acompound of Formula (Im), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is H and R¹³ is C₁₋₆alkyl. In another embodiment is a compound ofFormula (Im), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹² is H and R¹³ is—CH₃. In another embodiment is a compound of Formula (Im), or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹² is C₁₋₆alkyl and R¹³ is H. In anotherembodiment is a compound of Formula (Im), or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is —CH₃ and R¹³ is H. In another embodiment is acompound of Formula (Im), or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹²is C₁₋₆alkyl and R¹³ is C₁₋₆alkyl. In another embodiment is a compoundof Formula (Im), or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R¹² is —CH₃ and R¹³is —CH₃.

Further embodiments provided herein include combinations of one or moreof the particular embodiments set forth above.

In some embodiments, the compound disclosed herein is selected fromexamples 1-224.

In another embodiment is a compound having the structure:

wherein R⁴, R⁵, R⁶, R¹², and R¹³ are defined as in Formula (Ia)described herein, and x and y are at least one amino acid (aa). Inanother embodiment is a compound having the structure:

wherein R⁴, R⁵, R⁶, R¹², and R¹³ are defined as in Formula (Ia)described herein, and x and y are at least one amino acid (aa).

In another embodiment is a compound having the structure:

wherein R⁴, R⁵, R⁶, R¹², R¹³, and Z are defined as in Formula (Ib)described herein, and x and y are at least one amino acid (aa). Inanother embodiment is a compound having the structure:

wherein R⁴, R⁵, R⁶, R¹², R¹³, and Z are defined as in Formula (Ib)described herein, and x and y are at least one amino acid (aa).

In another embodiment is a compound having the structure:

wherein R⁴, R⁵, R¹², R¹³, and Z are defined as in Formula (Ic) describedherein, and x and y are at least one amino acid (aa). In anotherembodiment is a compound having the structure:

wherein R⁴, R⁵, R¹², R¹³, and Z are defined as in Formula (Ic) describedherein, and x and y are at least one amino acid (aa).

In another embodiment is a compound having the structure:

wherein R⁴, R⁵, R⁶, R¹², R¹³, A, Y, m, n, p, and w are defined as inFormula (Id) described herein, and x and y are at least one amino acid(aa). In another embodiment is a compound having the structure:

wherein R⁴, R⁵, R⁶, R¹², R¹³, A, Y, m, n, p, and w are defined as inFormula (Id) described herein, and x and y are at least one amino acid(aa).

In another embodiment is a compound having the structure:

wherein R⁴, R⁵, R⁶, R¹², R¹³, Y, Z, m, n, p, and q are defined as inFormula (Ie) described herein, and x and y are at least one amino acid(aa). In another embodiment is a compound having the structure:

wherein R⁴, R⁵, R⁶, R¹², R¹³, Y, Z, m, n, p, and q are defined as inFormula (Ie) described herein, and x and y are at least one amino acid(aa).

In another embodiment is a compound having the structure:

wherein R⁴, R⁵, R¹², R¹³, Y, Z, m, n, p, and q are defined as in Formula(If) described herein, and x and y are at least one amino acid (aa). Inanother embodiment is a compound having the structure:

wherein R⁴, R⁵, R¹², R¹³, Y, Z, m, n, p, and q are defined as in Formula(If) described herein, and x and y are at least one amino acid (aa).

In another embodiment is a compound having the structure:

wherein R⁴, R⁵, R⁶, R¹², R¹³, A, X, and v are defined as in Formula (Ig)described herein, and x and y are at least one amino acid (aa). Inanother embodiment is a compound having the structure:

wherein R⁴, R⁵, R⁶, R¹², R¹³, A, X, and v are defined as in Formula (Ig)described herein, and x and y are at least one amino acid (aa).

In another embodiment is a compound having the structure:

wherein R⁴, R⁵, R⁶, R¹², R¹³, A, X, and v are defined as in Formula (Ih)described herein, and x and y are at least one amino acid (aa). Inanother embodiment is a compound having the structure:

wherein R⁴, R⁵, R⁶, R¹², R¹³, A, X, and v are defined as in Formula (Ih)described herein, and x and y are at least one amino acid (aa).

In another embodiment is a compound having the structure:

wherein R⁴, R⁵, and R⁶ are defined as in Formula (Ii) described herein,and x and y are at least one amino acid (aa). In another embodiment is acompound having the structure:

wherein R⁴, R⁵, and R⁶ are defined as in Formula (Ii) described herein,and x and y are at least one amino acid (aa).

In another embodiment is a compound having the structure:

wherein R⁴, R⁵, R⁶, R¹², and R¹³ are defined as in Formula (Ij)described herein, and x and y are at least one amino acid (aa). Inanother embodiment is a compound having the structure:

wherein R⁴, R⁵, R⁶, R¹², and R¹³ are defined as in Formula (Ij)described herein, and x and y are at least one amino acid (aa).

In another embodiment is a compound having the structure:

wherein R⁴, R⁵, R⁶, R¹⁸, and R¹⁹ are defined as in Formula (Ik)described herein, and x and y are at least one amino acid (aa). Inanother embodiment is a compound having the structure:

wherein R⁴, R⁵, R⁶, R¹⁸, and R¹⁹ are defined as in Formula (Ik)described herein, and x and y are at least one amino acid (aa).

In another embodiment is a compound having the structure:

wherein R⁵, R⁶, R¹⁰, R¹², and R¹³ are defined as in Formula (Il)described herein, and x and y are at least one amino acid (aa). Inanother embodiment is a compound having the structure:

wherein R⁵, R⁶, R¹⁰, R¹², and R¹³ are defined as in Formula (Il)described herein, and x and y are at least one amino acid (aa).

In another embodiment is a compound having the structure:

wherein R⁵, R⁶, R¹⁰, R¹², and R¹³ are defined as in Formula (Im)described herein, and x and y are at least one amino acid (aa). Inanother embodiment is a compound having the structure:

wherein R⁵, R⁶, R¹⁰, R¹², and R¹³ are defined as in Formula (Im)described herein, and x and y are at least one amino acid (aa).

Described herein are inhibitors of monoacylglycerol lipase (MAGL) havingthe structure of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ih), (Ii), (Ij), (Ik), (Il), or (Im). In one embodiment, the inhibitorsof MAGL are covalent inhibitors of MAGL, that is, the compounds ofFormula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij),(Ik), (Il), or (Im) react with a serine residue of MAGL to form amodified serine residue, comprising the staying group of Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il),or (Im); in such an embodiment, the leaving group of Formula (I), (Ia),(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or(Im) is removed from the compound of Formula (I), (Ia), (Ib), (Ic),(Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im). In afurther embodiment, the covalent inhibitors of MAGL react irreversiblywith a serine residue of MAGL to form the modified serine residue.

The staying group portion of the compounds of Formula (Ia) is

The staying group portion of the compounds of Formula (Ib) is

The staying group portion of the compounds of Formula (Ic) is

The staying group portion of the compounds of Formula (Id) is

The staying group portion of the compounds of Formula (Ie) is

The staying group portion of the compounds of Formula (If) is

The staying group portion of the compounds of Formula (Ig) is

The staying group portion of the compounds of Formula (Ih) is

The staying group portion of the compounds of Formula (Ii) is

The staying group portion of the compounds of Formula (Ij) is

The staying group portion of the compounds of Formula (Ik) is

The staying group portion of the compounds of Formula (Il) is

The staying group portion of the compounds of Formula (Im) is

The leaving group portion of the compounds of Formula (I), (Ia), (Ib),(Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im) is:

Preparation of Compounds

The compounds used in the reactions described herein are made accordingto organic synthesis techniques, starting from commercially availablechemicals and/or from compounds described in the chemical literature.“Commercially available chemicals” are obtained from standard commercialsources including Acros Organics (Geel, Belgium), Aldrich Chemical(Milwaukee, Wis., including Sigma Chemical and Fluka), Apin ChemicalsLtd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville, Ill.), AvocadoResearch (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), Combi-blocks(San Diego, Calif.), Crescent Chemical Co. (Hauppauge, N.Y.), eMolecules(San Diego, Calif.), Fisher Scientific Co. (Pittsburgh, Pa.), FisonsChemicals (Leicestershire, UK), Frontier Scientific (Logan, Utah), ICNBiomedicals, Inc. (Costa Mesa, Calif.), Key Organics (Cornwall, U.K.),Lancaster Synthesis (Windham, N.H.), Matrix Scientific, (Columbia,S.C.), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co.(Orem, Utah), Pfaltz & Bauer, Inc. (Waterbury, Conn.), Polyorganix(Houston, Tex.), Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG(Hanover, Germany), Ryan Scientific, Inc. (Mount Pleasant, S.C.),Spectrum Chemicals (Gardena, Calif.), Sundia Meditech, (Shanghai,China), TCI America (Portland, Oreg.), Trans World Chemicals, Inc.(Rockville, Md.), and WuXi (Shanghai, China).

Suitable reference books and treatises that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additionalsuitable reference books and treatises that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts,Methods, Starting Materials”, Second, Revised and Enlarged Edition(1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “OrganicChemistry, An Intermediate Text” (1996) Oxford University Press, ISBN0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to theChemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9;Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley &Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate OrganicChemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;“Industrial Organic Chemicals: Starting Materials and Intermediates: AnUllmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X,in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in73 volumes.

Specific and analogous reactants are also identified through the indicesof known chemicals prepared by the Chemical Abstract Service of theAmerican Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (the AmericanChemical Society, Washington, D.C.). Chemicals that are known but notcommercially available in catalogs are optionally prepared by customchemical synthesis houses, where many of the standard chemical supplyhouses (e.g., those listed above) provide custom synthesis services. Areference for the preparation and selection of pharmaceutical salts ofthe compounds described herein is P. H. Stahl & C. G. Wermuth “Handbookof Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

Further Forms of Compounds Disclosed Herein Isomers

Furthermore, in some embodiments, the compounds described herein existas geometric isomers. In some embodiments, the compounds describedherein possess one or more double bonds. The compounds presented hereininclude all cis, trans, syn, anti, entgegen (E), and zusammen (Z)isomers as well as the corresponding mixtures thereof. In somesituations, compounds exist as tautomers. The compounds described hereininclude all possible tautomers within the formulas described herein. Insome situations, the compounds described herein possess one or morechiral centers and each center exists in the R configuration or Sconfiguration. The compounds described herein include alldiastereomeric, enantiomeric, and epimeric forms as well as thecorresponding mixtures thereof. In additional embodiments of thecompounds and methods provided herein, mixtures of enantiomers and/ordiastereoisomers, resulting from a single preparative step, combination,or interconversion, are useful for the applications described herein. Insome embodiments, the compounds described herein are prepared asoptically pure enantiomers by chiral chromatographic resolution of theracemic mixture. In some embodiments, the compounds described herein areprepared as their individual stereoisomers by reacting a racemic mixtureof the compound with an optically active resolving agent to form a pairof diastereoisomeric compounds, separating the diastereomers andrecovering the optically pure enantiomers. In some embodiments,dissociable complexes are preferred (e.g., crystalline diastereomericsalts). In some embodiments, the diastereomers have distinct physicalproperties (e.g., melting points, boiling points, solubilities,reactivity, etc.) and are separated by taking advantage of thesedissimilarities. In some embodiments, the diastereomers are separated bychiral chromatography, or preferably, by separation/resolutiontechniques based upon differences in solubility. In some embodiments,the optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that does not result inracemization.

Labeled Compounds

In some embodiments, the compounds described herein exist in theirisotopically-labeled forms. In some embodiments, the methods disclosedherein include methods of treating diseases by administering suchisotopically-labeled compounds. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch isotopically-labeled compounds as pharmaceutical compositions.Thus, in some embodiments, the compounds disclosed herein includeisotopically-labeled compounds, which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that areincorporated into compounds described herein include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, andchloride, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F,and ³⁶Cl, respectively. Compounds described herein, and pharmaceuticallyacceptable salts, esters, prodrugs, solvate, hydrates or derivativesthereof which contain the aforementioned isotopes and/or other isotopesof other atoms are within the scope of this invention. Certainisotopically-labeled compounds, for example those into which radioactiveisotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/orsubstrate tissue distribution assays. Tritiated, i. e., ³H andcarbon-14, i. e., ¹⁴C, isotopes are particularly preferred for theirease of preparation and detectability. Further, substitution with heavyisotopes such as deuterium, i.e., ²H, produces certain therapeuticadvantages resulting from greater metabolic stability, for exampleincreased in vivo half-life or reduced dosage requirements. In someembodiments, the isotopically labeled compounds, pharmaceuticallyacceptable salt, ester, prodrug, solvate, hydrate, or derivative thereofis prepared by any suitable method.

In some embodiments, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically Acceptable Salts

In some embodiments, the compounds described herein exist as theirpharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein possess acidic orbasic groups and therefore react with any of a number of inorganic ororganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. In some embodiments, these salts areprepared in situ during the final isolation and purification of thecompounds described herein, or by separately reacting a purifiedcompound in its free form with a suitable acid or base, and isolatingthe salt thus formed.

Solvates

In some embodiments, the compounds described herein exist as solvates.In some embodiments are methods of treating diseases by administeringsuch solvates. Further described herein are methods of treating diseasesby administering such solvates as pharmaceutical compositions.

Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and, in some embodiments, are formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Solvates of thecompounds described herein are conveniently prepared or formed duringthe processes described herein. By way of example only, hydrates of thecompounds described herein are conveniently prepared byrecrystallization from an aqueous/organic solvent mixture, using organicsolvents including, but not limited to, dioxane, tetrahydrofuran orMeOH. In addition, the compounds provided herein exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Prodrugs

In some embodiments, the compounds described herein exist in prodrugform. Also described herein are methods of treating diseases byadministering such prodrugs. Further described herein are methods oftreating diseases by administering such prodrugs as pharmaceuticalcompositions.

In some embodiments, prodrugs include compounds wherein an amino acidresidue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues is covalently joined through an amide or esterbond to a free amino, hydroxy, or carboxylic acid group of compoundsdescribed herein. The amino acid residues include but are not limited tothe 20 naturally occurring amino acids and also includes4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid,cirtulline, homocysteine, homoserine, ornithine, and methionine sulfone.In other embodiments, prodrugs include compounds wherein a nucleic acidresidue, or an oligonucleotide of two or more (e.g., two, three or four)nucleic acid residues is covalently joined to a compound describedherein.

Pharmaceutically acceptable prodrugs of the compounds described hereinalso include, but are not limited to, esters, carbonates,thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives,quaternary derivatives of tertiary amines, N-Mannich bases, Schiffbases, amino acid conjugates, phosphate esters, metal salts, andsulfonate esters. In some embodiments, compounds having free amino,amido, hydroxy, or carboxylic groups are converted into prodrugs. Forinstance, free carboxyl groups are derivatized as amides or alkylesters. In certain instances, all of these prodrug moieties incorporategroups including but not limited to ether, amine, and carboxylic acidfunctionalities.

Hydroxy prodrugs include esters, such as though not limited to,acyloxyalkyl (e.g. acyloxymethyl, acyloxyethyl) esters,alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphateesters, sulfonate esters, sulfate esters, disulfide containing esters,ethers, amides, carbamates, hemisuccinates, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews 1996, 19, 115.

Amine derived prodrugs include, but are not limited to the followinggroups and combinations of groups:

as well as sulfonamides and phosphonamides.

In certain instances, sites on any aromatic ring portions aresusceptible to various metabolic reactions, therefore incorporation ofappropriate substituents on the aromatic ring structures, reduce,minimize or eliminate this metabolic pathway.

Pharmaceutical Compositions

In certain embodiments, the compound of Formula (I), (Ia), (Ib), (Ic),(Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im) asdescribed herein is administered as a pure chemical. In someembodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im) described herein iscombined with a pharmaceutically suitable or acceptable carrier (alsoreferred to herein as a pharmaceutically suitable (or acceptable)excipient, physiologically suitable (or acceptable) excipient, orphysiologically suitable (or acceptable) carrier) selected on the basisof a chosen route of administration and standard pharmaceutical practiceas described, for example, in Remington: The Science and Practice ofPharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co., Easton, Pa. (2005)).

Accordingly, provided herein is a pharmaceutical composition comprisingat least one compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im) described herein, or astereoisomer, pharmaceutically acceptable salt, hydrate, solvate, orN-oxide thereof, together with one or more pharmaceutically acceptablecarriers. The carrier(s) (or excipient(s)) is acceptable or suitable ifthe carrier is compatible with the other ingredients of the compositionand not deleterious to the recipient (i.e., the subject) of thecomposition.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of Formula (I), ora pharmaceutically acceptable salt thereof. Another embodiment providesa pharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound of Formula (Ia), or a pharmaceuticallyacceptable salt thereof. Another embodiment provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient and acompound of Formula (Ib), or a pharmaceutically acceptable salt thereof.Another embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of Formula (Ic), ora pharmaceutically acceptable salt thereof. Another embodiment providesa pharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound of Formula (Id), or a pharmaceuticallyacceptable salt thereof. Another embodiment provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient and acompound of Formula (Ie), or a pharmaceutically acceptable salt thereof.Another embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of Formula (If), ora pharmaceutically acceptable salt thereof. Another embodiment providesa pharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound of Formula (Ig), or a pharmaceuticallyacceptable salt thereof. Another embodiment provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient and acompound of Formula (Ih), or a pharmaceutically acceptable salt thereof.Another embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of Formula (Ii), ora pharmaceutically acceptable salt thereof.

Another embodiment provides a pharmaceutical composition consistingessentially of a pharmaceutically acceptable excipient and a compound ofFormula (Ia), or a pharmaceutically acceptable salt thereof. Anotherembodiment provides a pharmaceutical composition consisting essentiallyof a pharmaceutically acceptable excipient and a compound of Formula(Ib), or a pharmaceutically acceptable salt thereof. Another embodimentprovides a pharmaceutical composition consisting essentially of apharmaceutically acceptable excipient and a compound of Formula (Ic), ora pharmaceutically acceptable salt thereof. Another embodiment providesa pharmaceutical composition consisting essentially of apharmaceutically acceptable excipient and a compound of Formula (Id), ora pharmaceutically acceptable salt thereof. Another embodiment providesa pharmaceutical composition consisting essentially of apharmaceutically acceptable excipient and a compound of Formula (Ie), ora pharmaceutically acceptable salt thereof. Another embodiment providesa pharmaceutical composition consisting essentially of apharmaceutically acceptable excipient and a compound of Formula (If), ora pharmaceutically acceptable salt thereof. Another embodiment providesa pharmaceutical composition consisting essentially of apharmaceutically acceptable excipient and a compound of Formula (Ig), ora pharmaceutically acceptable salt thereof. Another embodiment providesa pharmaceutical composition consisting essentially of apharmaceutically acceptable excipient and a compound of Formula (Ih), ora pharmaceutically acceptable salt thereof. Another embodiment providesa pharmaceutical composition consisting essentially of apharmaceutically acceptable excipient and a compound of Formula (Ii), ora pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I), (Ia), (Ib), (Ic),(Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im) asdescribed herein is substantially pure, in that it contains less thanabout 5%, or less than about 1%, or less than about 0.1%, of otherorganic small molecules, such as contaminating intermediates orby-products that are created, for example, in one or more of the stepsof a synthesis method.

These formulations include those suitable for oral, rectal, topical,buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, orintravenous), vaginal, ophthalmic, or aerosol administration, althoughthe most suitable form of administration in any given case will dependon the degree and severity of the condition being treated and on thenature of the particular compound being used. For example, disclosedcompositions are formulated as a unit dose, and/or are formulated fororal or subcutaneous administration.

Exemplary pharmaceutical compositions are used in the form of apharmaceutical preparation, for example, in solid, semisolid or liquidform, which includes one or more of a disclosed compound, as an activeingredient, in a mixture with an organic or inorganic carrier orexcipient suitable for external, enteral or parenteral applications. Insome embodiments, the active ingredient is compounded, for example, withthe usual non-toxic, pharmaceutically acceptable carriers for tablets,pellets, capsules, suppositories, solutions, emulsions, suspensions, andany other form suitable for use. The active object compound is includedin the pharmaceutical composition in an amount sufficient to produce thedesired effect upon the process or condition of the disease.

In some embodiments for preparing solid compositions such as tablets,the principal active ingredient is mixed with a pharmaceutical carrier,e.g., conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate, or gums, and other pharmaceutical diluents, e.g., water, toform a solid preformulation composition containing a homogeneous mixtureof a disclosed compound or a non-toxic pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition is readily subdividedinto equally effective unit dosage forms such as tablets, pills andcapsules.

In solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules and the like), the subject composition ismixed with one or more pharmaceutically acceptable carriers, such assodium citrate or dicalcium phosphate, and/or any of the following: (1)fillers or extenders, such as starches, cellulose, microcrystallinecellulose, silicified microcrystalline cellulose, lactose, sucrose,glucose, mannitol, and/or silicic acid; (2) binders, such as, forexample, carboxymethylcellulose, hypromellose, alginates, gelatin,polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such asglycerol; (4) disintegrating agents, such as crospovidone,croscarmellose sodium, sodium starch glycolate, agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate; (5) solution retarding agents, such as paraffin;(6) absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, docusate sodium, cetyl alcohol andglycerol monostearate; (8) absorbents, such as kaolin and bentoniteclay; (9) lubricants, such a talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof;and (10) coloring agents. In the case of capsules, tablets and pills, insome embodiments, the compositions comprise buffering agents. In someembodiments, solid compositions of a similar type are also employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

In some embodiments, a tablet is made by compression or molding,optionally with one or more accessory ingredients. In some embodiments,compressed tablets are prepared using binder (for example, gelatin orhydroxypropylmethyl cellulose), lubricant, inert diluent, preservative,disintegrant (for example, sodium starch glycolate or cross-linkedsodium carboxymethyl cellulose), surface-active or dispersing agent. Insome embodiments, molded tablets are made by molding in a suitablemachine a mixture of the subject composition moistened with an inertliquid diluent. In some embodiments, tablets, and other solid dosageforms, such as dragees, capsules, pills, and granules, are scored orprepared with coatings and shells, such as enteric coatings and othercoatings.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable aqueous or organic solvents,or mixtures thereof, and powders. Liquid dosage forms for oraladministration include pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the subject composition, in some embodiments, the liquid dosage formscontain inert diluents, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (optionally,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, cyclodextrins and mixtures thereof.

In some embodiments, suspensions, in addition to the subjectcomposition, contain suspending agents as, for example, ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,microcrystalline cellulose, aluminum metahydroxide, bentonite,agar-agar, tragacanth, and mixtures thereof.

In some embodiments, formulations for rectal or vaginal administrationare presented as a suppository, which are prepared by mixing a subjectcomposition with one or more suitable non-irritating excipients orcarriers comprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the bodycavity and release the active agent.

Dosage forms for transdermal administration of a subject compositioninclude powders, sprays, ointments, pastes, creams, lotions, gels,solutions, patches and inhalants. In some embodiments, the activecomponent is mixed under sterile conditions with a pharmaceuticallyacceptable carrier, and with any preservatives, buffers, or propellantsas required.

In some embodiments, the ointments, pastes, creams and gels contain, inaddition to a subject composition, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc, and zinc oxide, or mixtures thereof.

In some embodiments, powders and sprays contain, in addition to asubject composition, excipients such as lactose, talc, silicic acid,aluminum hydroxide, calcium silicates and polyamide powder, or mixturesof these substances. In some embodiments, sprays additionally containcustomary propellants, such as chlorofluorohydrocarbons and volatileunsubstituted hydrocarbons, such as butane and propane.

In some embodiments, the compounds described herein are formulated aseye drops for ophthalmic administration.

Compositions and compounds disclosed herein alternatively areadministered by aerosol. This is accomplished by preparing an aqueousaerosol, liposomal preparation or solid particles containing thecompound. In some embodiments, a non-aqueous (e.g., fluorocarbonpropellant) suspension is used. In some embodiments, sonic nebulizersare used because they minimize exposing the agent to shear, whichresults in degradation of the compounds contained in the subjectcompositions. Ordinarily, an aqueous aerosol is made by formulating anaqueous solution or suspension of a subject composition together withconventional pharmaceutically acceptable carriers and stabilizers. Thecarriers and stabilizers vary with the requirements of the particularsubject composition, but typically include non-ionic surfactants(Tweens, Pluronics, or polyethylene glycol), innocuous proteins likeserum albumin, sorbitan esters, oleic acid, lecithin, amino acids suchas glycine, buffers, salts, sugars or sugar alcohols. Aerosols generallyare prepared from isotonic solutions.

Pharmaceutical compositions suitable for parenteral administrationcomprise a subject composition in combination with one or morepharmaceutically-acceptable sterile isotonic aqueous or non-aqueoussolutions, dispersions, suspensions or emulsions, or sterile powderswhich are reconstituted into sterile injectable solutions or dispersionsjust prior to use, which, in some embodiments, contain antioxidants,buffers, bacteriostats, solutes which render the formulation isotonicwith the blood of the intended recipient or suspending or thickeningagents.

Examples of suitable aqueous and non-aqueous carriers which are employedin the pharmaceutical compositions include water, ethanol, polyols (suchas glycerol, propylene glycol, polyethylene glycol, and the like), andsuitable mixtures thereof, vegetable oils such as olive oil, andinjectable organic esters such as ethyl oleate and cyclodextrins. Properfluidity is maintained, for example, by the use of coating materials,such as lecithin, by the maintenance of the required particle size inthe case of dispersions, and by the use of surfactants.

Also contemplated are enteral pharmaceutical formulations including adisclosed compound, an enteric material, and a pharmaceuticallyacceptable carrier or excipient thereof. Enteric materials refer topolymers that are substantially insoluble in the acidic environment ofthe stomach, and that are predominantly soluble in intestinal fluids atspecific pHs. The small intestine is the part of the gastrointestinaltract (gut) between the stomach and the large intestine, and includesthe duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5,the pH of the jejunum is about 6.5 and the pH of the distal ileum isabout 7.5. Accordingly, enteric materials are not soluble, for example,until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, ofabout 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, ofabout 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, ofabout 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, ofabout 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, ofabout 9.8, or of about 10.0. Exemplary enteric materials includecellulose acetate phthalate (CAP), hydroxypropyl methylcellulosephthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetatetrimellitate, hydroxypropyl methylcellulose succinate, cellulose acetatesuccinate, cellulose acetate hexahydrophthalate, cellulose propionatephthalate, cellulose acetate maleate, cellulose acetate butyrate,cellulose acetate propionate, copolymer of methylmethacrylic acid andmethyl methacrylate, copolymer of methyl acrylate, methylmethacrylateand methacrylic acid, copolymer of methylvinyl ether and maleicanhydride (Gantrez ES series), ethylmethyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylatecopolymer, natural resins such as zein, shellac and copal collophorium,and several commercially available enteric dispersion systems (e.g.,Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, KollicoatEMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of eachof the above materials is either known or is readily determinable invitro.

The dose of the composition comprising at least one compound of Formula(I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik),(Il), or (Im) as described herein differs, depending upon the patient's(e.g., human) condition, that is, stage of the disease, general healthstatus, age, and other factors.

Pharmaceutical compositions are administered in a manner appropriate tothe disease to be treated (or prevented). An appropriate dose and asuitable duration and frequency of administration will be determined bysuch factors as the condition of the patient, the type and severity ofthe patient's disease, the particular form of the active ingredient, andthe method of administration. In general, an appropriate dose andtreatment regimen provides the composition(s) in an amount sufficient toprovide therapeutic and/or prophylactic benefit (e.g., an improvedclinical outcome, such as more frequent complete or partial remissions,or longer disease-free and/or overall survival, or a lessening ofsymptom severity. Optimal doses are generally determined usingexperimental models and/or clinical trials. In some embodiments, theoptimal dose depends upon the body mass, weight, or blood volume of thepatient.

Oral doses typically range from about 1.0 mg to about 1000 mg, one tofour times, or more, per day.

Methods

Disclosed herein are methods of modulating the activity of MAGL.Contemplated methods, for example, comprise exposing said enzyme to acompound described herein. In some embodiments, the compound utilized byone or more of the foregoing methods is one of the generic, subgeneric,or specific compounds described herein, such as a compound of Formula(I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik),(Il), or (Im). In some embodiments, provided herein is a compound ofFormula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij),(Ik), (Il), or (Im) wherein the compound is a MAGL inhibitor. In someembodiments, provided herein is a compound of Formula (I), (Ia), (Ib),(Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im)wherein the compound is a selective MAGL inhibitor. Another aspect ofthis disclosure provides methods of treating a disease associated withexpression or activity of MAGL in a patient. In some embodiments,provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (Id),(Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im) wherein thecompound is selective in inhibiting MAGL as compared to inhibition ofother serine hydrolases. In some embodiments, provided herein is acompound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih),(Ii), (Ij), (Ik), (Il), or (Im) wherein the compound is 10, 100, or 1000fold selective in inhibiting MAGL as compared to inhibition of otherserine hydrolases.

In another embodiment is a method of treating pain in a patient,comprising administering a therapeutically effective amount of acompound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih),(Ii), (Ij), (Ik), (Il), or (Im) described herein, or a solvate, hydrate,tautomer, N-oxide, or a pharmaceutically acceptable salt thereof, to apatient in need thereof to treat said pain. In another embodiment is amethod of treating neuropathic pain in a patient, comprisingadministering a therapeutically effective amount of a compound ofFormula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij),(Ik), (Il), or (Im) described herein, or a solvate, hydrate, tautomer,N-oxide, or a pharmaceutically acceptable salt thereof, to a patient inneed thereof to treat said neuropathic pain. In another embodiment is amethod of treating inflammatory pain in a patient, comprisingadministering a therapeutically effective amount of a compound ofFormula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij),(Ik), (Il), or (Im) described herein, or a solvate, hydrate, tautomer,N-oxide, or a pharmaceutically acceptable salt thereof, to a patient inneed thereof to treat said inflammatory pain.

Also contemplated herein in some embodiments are methods of treatingand/or preventing in a patient in need thereof a disorder such as one ormore of acute or chronic pain, bone cancer pain, rheumatoid arthritispain, pruritus, vomiting or nausea, Down's syndrome, Parkinson'sdisease, epilepsy, NSAID-induced ulcers, opioid withdrawal, cannabiswithdrawal, nicotine withdrawal, traumatic brain injury, ischemia, renalischemia, cancers (e.g., solid tumor cancers such as breast, lung, headand neck, ovarian, sarcoma, melanoma, and/or prostate cancer); cancerssuch as melanoma, metastatic tumors, kidney or bladder cancers, brain,gastrointestinal cancers (e.g., colon cancer), leukemia or blood cancers(e.g., myeloid, lymphoid or monocytic cancers), liver injury, lunginjury, skeletal muscle contusions, inflammatory disorders, and/oranxiety disorders. Contemplated methods include administering apharmaceutically effective amount of a disclosed compound.

In some embodiments, provided herein is a method for treating,ameliorating and/or preventing damage from ischemia, for example,hepatic ischemia or reperfusion in a patient in need thereof, comprisingadministering a disclosed compound. Methods of treating patients withliver conditions resulting from oxidative stress and/or inflammatorydamage are contemplated herein, e.g., contemplated herein are methods oftreating liver fibrosis, iron overload, and/or corticosteroid therapythat result in liver damage, in a patient in need thereof.

In some embodiments, provide herein is a method for treating chronicpain such as inflammatory pain, visceral pain, back pain, post operativepain, and pain related to migraine, osteoarthritis, or rheumatoidarthritis.

In some embodiments, provide herein are methods for amelioratingcognitive function in a patient suffering from Down's syndrome orAlzheimer's disease, comprising administering an effective amount of adisclosed compound. Exemplary patients suffering from Down's syndromeare a pediatric patient (e.g., a patient of age 0-11 years, 0-18 years,0-6 years, or e.g., 12 to 18 years), an adult patient (e.g., 18 years orolder), or e.g., an older patient e.g., 18-40 years, 20-50 years). Insome embodiments, such patients also suffer from further cognitiveimpairment and/or dementia, and/or seizures which, in some embodimentsare due to production of prostaglandins and/or amyloid beta. Forexample, such patients also are suffering from, or have one or more ofthe following symptoms associated with early- mid or late stagecognitive impairment: loss of language, impairment of social skills,progressive loss of activities of daily living, and include psychoticbehavior. Provided herein, for example, is a method for treating apatient having Down's syndrome or Alzheimer's disease with cognitiveimpairment, comprising administering an effective amount of a disclosedcompound. Such disclosed methods result in cognitive improvement, forexample, measured by IQ or the Arizona Cognitive Test Battery (e.g.,measured with a cognitive test battery designed for use in individualswith Down's syndrome). For example, a treated patient using a disclosedmethod has at least one of: increased memory, improved memory orimproved speech. In some embodiments, such disclosed methods result in apatient having an increased quality of life as measured by an adaptivebehavior scale after said administration.

In other embodiments, a method for at least partially providing a Down'ssyndrome patient a neuroprotective (such as a disclosed compounds), thatresults in delayed onset of neurodegeneration or substantially preventsneurodegeneration, is provided. Administration to a patient is initiatedbefore onset of neurodegeneration and/or onset of neurodegenerationsymptoms. Contemplated herein are methods for treating and/orameliorating cognitive decline, improving sleep duration and/or quality,and/or treating PANDAS (pediatric autoimmune neuropsychiatric disordersassociated with streptococcal infections) in a patient in need thereof,comprising administering a disclosed compound.

In another embodiment is a method of treating a disease or disorder in apatient in need thereof, comprising administering to the patient in needthereof a therapeutically effective amount of a compound of Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il),or (Im) described herein, or a pharmaceutically acceptable salt orsolvate thereof, wherein the disease or disorder is selected from thegroup consisting of migraine, epilepsy/seizure disorder, neuromyelitisoptica (NMO), Tourette syndrome, persistent motor tic disorder,persistent vocal tic disorder, and abdominal pain associated withirritable bowel syndrome. In another embodiment is a method of treatingmigraine in a patient in need thereof, comprising administering to thepatient a therapeutically effective amount of a compound of Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il),or (Im) described herein, or a pharmaceutically acceptable salt orsolvate thereof. In another embodiment is a method of treatingepilepsy/seizure disorder in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih),(Ii), (Ij), (Ik), (Il), or (Im) described herein, or a pharmaceuticallyacceptable salt or solvate thereof. In another embodiment is a method oftreating neuromyelitis optica (NMO) in a patient in need thereof,comprising administering to the patient a therapeutically effectiveamount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If),(Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im) described herein, or apharmaceutically acceptable salt or solvate thereof. In anotherembodiment is a method of treating Tourette syndrome in a patient inneed thereof, comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id),(Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im) describedherein, or a pharmaceutically acceptable salt or solvate thereof. Inanother embodiment is a method of treating persistent motor tic disorderin a patient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or(Im) described herein, or a pharmaceutically acceptable salt or solvatethereof. In another embodiment is a method of treating persistent vocaltic disorder in a patient in need thereof, comprising administering tothe patient a therapeutically effective amount of a compound of Formula(I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik),(Il), or (Im) described herein, or a pharmaceutically acceptable salt orsolvate thereof. In another embodiment is a method of treating abdominalpain associated with irritable bowel syndrome in a patient in needthereof, comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id),(Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im) describedherein, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment is a method of treating cancer pain, pain causedby peripheral neuropathy, central pain, fibromyalgia, migraine,vasoocclussive painful crises in sickle cell disease, functional chestpain, rheumatoid arthritis, osteoarthritis, functional dyspepsia, orspasticity, pain, sleep disturbance, or bladder dysfunction associatedwith multiple sclerosis, in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih),(Ii), (Ij), (Ik), (Il), or (Im) described herein, or a pharmaceuticallyacceptable salt or solvate thereof. In another embodiment is a method oftreating cancer pain in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih),(Ii), (Ij), (Ik), (Il), or (Im) described herein, or a pharmaceuticallyacceptable salt or solvate thereof. In another embodiment is a method oftreating pain caused by peripheral neuropathy in a patient in needthereof, comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id),(Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im) describedherein, or a pharmaceutically acceptable salt or solvate thereof. Inanother embodiment is a method of treating central pain in a patient inneed thereof, comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id),(Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im) describedherein, or a pharmaceutically acceptable salt or solvate thereof. Inanother embodiment is a method of treating fibromyalgia in a patient inneed thereof, comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id),(Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im) describedherein, or a pharmaceutically acceptable salt or solvate thereof. Inanother embodiment is a method of treating migraine in a patient in needthereof, comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id),(Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im) describedherein, or a pharmaceutically acceptable salt or solvate thereof. Inanother embodiment is a method of treating vasoocclussive painful crisesin sickle cell disease in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih),(Ii), (Ij), (Ik), (Il), or (Im) described herein, or a pharmaceuticallyacceptable salt or solvate thereof. In another embodiment is a method oftreating spasticity, pain, sleep disturbance, or bladder dysfunctionassociated with multiple sclerosis in a patient in need thereof,comprising administering to the patient a therapeutically effectiveamount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If),(Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im) described herein, or apharmaceutically acceptable salt or solvate thereof. In anotherembodiment is a method of treating functional chest pain in a patient inneed thereof, comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id),(Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im) describedherein, or a pharmaceutically acceptable salt or solvate thereof. Inanother embodiment is a method of treating rheumatoid arthritis in apatient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or(Im) described herein, or a pharmaceutically acceptable salt or solvatethereof. In another embodiment is a method of treating osteoarthritis ina patient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or(Im) described herein, or a pharmaceutically acceptable salt or solvatethereof. In another embodiment is a method of treating functionaldyspepsia in a patient in need thereof, comprising administering to thepatient a therapeutically effective amount of a compound of Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il),or (Im) described herein, or a pharmaceutically acceptable salt orsolvate thereof.

In another embodiment is a method of lowering intraocular eye pressure(TOP) in a patient in need thereof, comprising administering to thepatient a therapeutically effective amount of a compound of Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il),or (Im) described herein, or a pharmaceutically acceptable salt orsolvate thereof. In another embodiment is a method of treating glaucomain a patient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or(Im) described herein, or a pharmaceutically acceptable salt or solvatethereof.

In another embodiment is a method of treating atopic dermatitis in apatient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or(Im) described herein, or a pharmaceutically acceptable salt or solvatethereof.

In another embodiment is a method of treating pruritis in a patient inneed thereof, comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id),(Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or (Im) describedherein, or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, disclosed herein is a method of synergisticallypotentiating the activity of an opioid analgesic in a patient beingtreated with an opioid analgesic, comprising administering to thepatient a therapeutically effective amount of a compound of Formula (I),(Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il),or (Im) described herein, or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, disclosed herein is a method ofreducing the acute side-effects associated with an opioid analgesic in apatient being treated with an opioid analgesic, comprising administeringto the patient a therapeutically effective amount of a compound ofFormula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij),(Ik), (Il), or (Im) described herein, or a pharmaceutically acceptablesalt or solvate thereof.

In certain embodiments, a disclosed compound utilized by one or more ofthe foregoing methods is one of the generic, subgeneric, or specificcompounds described herein, such as a compound of Formula (I), (Ia),(Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), or(Im).

Disclosed compounds are administered to patients (animals and humans) inneed of such treatment in dosages that will provide optimalpharmaceutical efficacy. It will be appreciated that the dose requiredfor use in any particular application will vary from patient to patient,not only with the particular compound or composition selected, but alsowith the route of administration, the nature of the condition beingtreated, the age and condition of the patient, concurrent medication orspecial diets then being followed by the patient, and other factors,with the appropriate dosage ultimately being at the discretion of theattendant physician. For treating clinical conditions and diseases notedabove, a contemplated compound disclosed herein is administered orally,subcutaneously, topically, parenterally, by inhalation spray, orrectally in dosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles. Parenteraladministration include subcutaneous injections, intravenous, orintramuscular injections or infusion techniques.

Also contemplated herein are combination therapies, for example,co-administering a disclosed compound and an additional active agent, aspart of a specific treatment regimen intended to provide the beneficialeffect from the co-action of these therapeutic agents. The beneficialeffect of the combination includes, but is not limited to,pharmacokinetic or pharmacodynamic co-action resulting from thecombination of therapeutic agents. Administration of these therapeuticagents in combination typically is carried out over a defined timeperiod (usually weeks, months or years depending upon the combinationselected). Combination therapy is intended to embrace administration ofmultiple therapeutic agents in a sequential manner, that is, whereineach therapeutic agent is administered at a different time, as well asadministration of these therapeutic agents, or at least two of thetherapeutic agents, in a substantially simultaneous manner.

Substantially simultaneous administration is accomplished, for example,by administering to the subject a single formulation or composition,(e.g., a tablet or capsule having a fixed ratio of each therapeuticagent or in multiple, single formulations (e.g., capsules) for each ofthe therapeutic agents. Sequential or substantially simultaneousadministration of each therapeutic agent is effected by any appropriateroute including, but not limited to, oral routes, intravenous routes,intramuscular routes, and direct absorption through mucous membranetissues. The therapeutic agents are administered by the same route or bydifferent routes. For example, a first therapeutic agent of thecombination selected is administered by intravenous injection while theother therapeutic agents of the combination are administered orally.Alternatively, for example, all therapeutic agents are administeredorally or all therapeutic agents are administered by intravenousinjection.

Combination therapy also embraces the administration of the therapeuticagents as described above in further combination with other biologicallyactive ingredients and non-drug therapies. Where the combination therapyfurther comprises a non-drug treatment, the non-drug treatment isconducted at any suitable time so long as a beneficial effect from theco-action of the combination of the therapeutic agents and non-drugtreatment is achieved. For example, in appropriate cases, the beneficialeffect is still achieved when the non-drug treatment is temporallyremoved from the administration of the therapeutic agents, perhaps bydays or even weeks.

The components of the combination are administered to a patientsimultaneously or sequentially. It will be appreciated that thecomponents are present in the same pharmaceutically acceptable carrierand, therefore, are administered simultaneously. Alternatively, theactive ingredients are present in separate pharmaceutical carriers, suchas, conventional oral dosage forms, that are administered eithersimultaneously or sequentially.

In some embodiments, for contemplated treatment of pain, a disclosedcompound is co-administered with another therapeutic for pain such as anopioid, a cannabinoid receptor (CB-1 or CB-2) modulator, a COX-2inhibitor, acetaminophen, and/or a non-steroidal anti-inflammatoryagent. Additional therapeutics e.g., for the treatment of pain that areco-administered include morphine, codeine, hydromorphone, hydrocodone,oxymorphone, fentanyl, tramadol, and levorphanol.

Other contemplated therapeutics for co-administration include aspirin,naproxen, ibuprofen, salsalate, diflunisal, dexibuprofen, fenoprofen,ketoprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac,etodolac, ketorolac, piroxicam, meloxicam, tenoxicam, droxicam,lornoxicam, celecoxib, parecoxib, rimonabant, and/or etoricoxib.

The following examples are provided merely as illustrative of variousembodiments and shall not be construed to limit the invention in anyway.

EXAMPLES List of Abbreviations

As used above, and throughout the description of the invention, thefollowing abbreviations, unless otherwise indicated, shall be understoodto have the following meanings:

-   -   ACN or MeCN acetonitrile    -   Bn benzyl    -   BOC or Boc tent-butyl carbamate    -   CDI 1,1′-carbonyldiimidazole    -   Cy cyclohexyl    -   DCE dichloroethane (ClCH₂CH₂Cl)    -   DCM dichloromethane (CH₂Cl₂)    -   DIPEA or DIEA diisopropylethylamine    -   DMAP 4-(N,N-dimethylamino)pyridine    -   DMF dimethylformamide    -   DMA N,N-dimethylacetamide    -   DMSO dimethylsulfoxide    -   equiv equivalent(s)    -   Et ethyl    -   EtOH ethanol    -   EtOAc ethyl acetate    -   HATU        1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxid hexafluorophosphate    -   HPLC high performance liquid chromatography    -   LAH lithium aluminum hydride    -   Me methyl    -   MeOH methanol    -   MS mass spectroscopy    -   NMM N-methylmorpholine    -   NMR nuclear magnetic resonance    -   PMB para-methoxybenzyl    -   TEA triethylamine    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   TLC thin layer chromatography

I. Chemical Synthesis

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Anhydrous solvents and oven-dried glassware wereused for synthetic transformations sensitive to moisture and/or oxygen.Yields were not optimized. Reaction times are approximate and were notoptimized. Column chromatography and thin layer chromatography (TLC)were performed on silica gel unless otherwise noted. Spectra are givenin ppm (δ) and coupling constants (J) are reported in Hertz. For protonspectra the solvent peak was used as the reference peak.

Example 14-((2-((8-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)-1,8-diazaspiro[4.5]decan-1-yl)methyl)-5-(trifluoromethyl)phenyl)amino)butanoicacid

Step 1: Preparation of t-butyl 4-((4-methoxybenzyl)amino)butanoate

A flask was charged with 4-methoxybenzaldehyde (4.27 g, 31.4 mmol, 1.00equiv), ethanol (30 mL), and t-butyl 4-aminobutanoate (5.00 g, 31.4mmol, 1.00 equiv). The resulting solution was stirred 5 h at 70° C. andcooled to room temperature. Sodium borohydride (0.718 g, 18.9 mmol, 0.60equiv) was added. The resulting solution was stirred overnight at roomtemperature and concentrated under reduced pressure. The residue waschromatographed to provide 4.55 g (52% yield) of t-butyl4-((4-methoxybenzyl)amino)butanoate as a yellow oil. LCMS (ESI, m/z):280 [M+H]⁺.

Step 2: Preparation of t-butyl4-((2-formyl-5-(trifluoromethyl)phenyl)(4-methoxybenzyl)amino)butanoate

A flask was charged with t-butyl 4-((4-methoxybenzyl)amino)butanoate(3.00 g, 10.7 mmol, 1.00 equiv), DMSO (35 mL),2-fluoro-4-(trifluoromethyl)benzaldehyde (2.07 g, 10.7 mmol, 1.00equiv), and DIPEA (4.18 g, 32.3 mmol, 3.00 equiv) under nitrogen. Theresulting solution was stirred overnight at 110° C. and quenched withwater (50 mL). The resulting solution was extracted with DCM (2×80 mL)and the organic layers were combined, washed with brine (2×50 mL), driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was chromatographed on a silica gel column toprovide 2.20 g (45% yield) of t-butyl4-((2-formyl-5-(trifluoromethyl)phenyl)(4-methoxybenzyl)amino)butanoateas a yellow oil. LCMS (ESI, m/z): 452 [M+H]⁺.

Step 3: Preparation of 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate

A flask was charged with N-(1H-pyrazol-3-yl)methanesulfonamide (2.00 g,12.4 mmol, 1.00 equiv), DCM (40 mL), triethylamine (3.77 g, 37.3 mmol,3.00 equiv), and 4-nitrophenyl chloroformate (2.49 g, 12.4 mmol, 1.00equiv). The resulting solution was stirred for 1 h at room temperatureand concentrated under reduced pressure to provide 5.00 g (crude) of4-nitrophenyl 3-methanesulfonamido-1H-pyrazole-1-carboxylate as a yellowsolid. LCMS (ESI, m/z): 327 [M+H]⁺.

Step 4: Preparation of t-butyl8-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)-1,8-diazaspiro[4.5]decane-1-carboxylate

A flask was charged with 4-nitrophenyl3-methanesulfonamido-1H-pyrazole-1-carboxylate (3.65 g, 11.2 mmol, 1.00equiv), DCM (40 mL), t-butyl 1,8-diazaspiro[4.5]decane-1-carboxylate(3.24 g, 13.5 mmol, 1.20 equiv), and triethylamine (3.39 g, 33.6 mmol,3.00 equiv). The resulting solution was stirred overnight at roomtemperature and quenched with water (50 mL). The resulting solution wasextracted with DCM (2×80 mL) and the organic layers were combined,washed with brine (2×50 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waschromatographed on a silica gel column to provide 3.46 g (72% yield) oft-butyl8-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)-1,8-diazaspiro[4.5]decane-1-carboxylateas a yellow solid. LCMS (ESI, m/z): 428 [M+H]⁺.

Step 5: Preparation ofN-(1-(1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

A flask was charged with t-butyl8-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)-1,8-diazaspiro[4.5]decane-1-carboxylate(200 mg, 0.470 mmol, 1.00 equiv), DCM (10 mL), and TFA (2 mL). Theresulting solution was stirred for 3 h at room temperature andconcentrated under reduced pressure to provide 250 mg (crude) ofN-(1-(1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazol-3-yl)methanesulfonamideas a yellow oil. LCMS (ESI, m/z): 328 [M+H]⁺.

Step 6: Preparation of t-butyl4-((4-methoxybenzyl)(2-((8-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)-1,8-diazaspiro[4.5]decan-1-yl)methyl)-5-(trifluoromethyl)phenyl)amino)butanoate

A flask was charged withN-(1-(1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide(153 mg, 0.470 mmol, 1.20 equiv), DCM (10 mL), triethylamine (118 mg,1.17 mmol, 3.00 equiv), and t-butyl4-((2-formyl-5-(trifluoromethyl)phenyl)(4-methoxybenzyl)amino)butanoate(177 mg, 0.390 mmol, 1.00 equiv). Sodium triacetoxyborohydride (248 mg,1.17 mmol, 3.00 equiv) was added. The resulting solution was stirredovernight at room temperature and quenched with water (30 mL). Theresulting solution was extracted with DCM (2×50 mL) and the organiclayers were combined, washed with brine (2×30 mL), dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was chromatographed on a silica gel column to provide 220 mg(74% yield) of t-butyl4-((4-methoxybenzyl)(2-((8-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)-1,8-diazaspiro[4.5]decan-1-yl)methyl)-5-(trifluoromethyl)phenyl)amino)butanoateas yellow oil. LCMS (ESI, m/z): 763 [M+H]⁺.

Step 7: Preparation of4-((2-((8-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)-1,8-diazaspiro[4.5]decan-1-yl)methyl)-5-(trifluoromethyl)phenyl)amino)butanoicacid

A flask was charged with t-butyl4-((4-methoxybenzyl)(2-((8-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)-1,8-diazaspiro[4.5]decan-1-yl)methyl)-5-(trifluoromethyl)phenyl)amino)butanoate(220 mg, 0.290 mmol, 1.00 equiv), DCM (10 mL), and TFA (2 mL). Theresulting solution was stirred for 5 h at room temperature andconcentrated under reduced pressure. The crude product (400 mg) waspurified by preparative HPLC to provide 23.0 mg (14% yield) of4-((2-((8-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)-1,8-diazaspiro[4.5]decan-1-yl)methyl)-5-(trifluoromethyl)phenyl)amino)butanoicacid as a white solid.

¹H NMR (400 MHz, Methanol-d₄) 8.04 (d, J=2.8 Hz, 1H), 7.16 (d, J=7.6 Hz,1H), 6.83-6.89 (m, 1H), 6.76 (s,1H), 6.25 (d, J=2.8 Hz, 1H), 4.57-4.59(m, 2H), 3.78 (s , 2H), 3.11-3.18 (m, 7H), 2.63 (t, J=7.0 Hz, 2H), 2.41(t, J=7.4 Hz, 2H), 2.01-2.12 (m, 2H), 1.90-1.99 (m, 4H), 1.77-1.85 (m,2H), 1.51-1.59 (m, 2H). LCMS (ESI, m/z): 587 [M+H]⁺.

Example 2N-(1-(4-((3-(4-fluoropiperidin-1-yl)-4-(trifluoromethyl)benzyl)(methyl)amino)-4-methylpiperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

Step 1: Preparation of t-butyl4-((3-bromo-4-(trifluoromethyl)benzyl)amino)-4-methylpiperidine-1-carboxylate

A vial was charged with DCE (10 mL),3-bromo-4-(trifluoromethyl)benzaldehyde (252 mg, 1.00 mmol, 1.00 equiv),t-butyl 4-amino-4-methylpiperidine-1-carboxylate (214 mg, 1.00 mmol,1.00 equiv), and triethylamine (303 mg, 2.99 mmol, 3.00 equiv). Theresulting solution was stirred for 1 h at room temperature, then sodiumtriacetoxyborohydride (636 mg, 3.00 mmol, 3.00 equiv) was added. Themixture was stirred overnight at room temperature and quenched withwater (10 mL), as described in Example 1, Step 6. The residue waschromatographed on a silica gel column to provide 300 mg (67% yield) oft-butyl4-((3-bromo-4-(trifluoromethyl)benzyl)amino)-4-methylpiperidine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 451 [M+H]⁺.

Step 2: Preparation of t-butyl4-((3-bromo-4-(trifluoromethyl)benzyl)(methyl)amino)-4-methylpiperidine-1-carboxylate

A vial was charged with DCE (10 mL), t-butyl4-((3-bromo-4-(trifluoromethyl)benzyl)amino)-4-methylpiperidine-1-carboxylate(300 mg, 0.660 mmol, 1.00 equiv), and paraformaldehyde (200 mg, 6.67mmol, 10.00 equiv). The resulting solution was stirred for 1 h at roomtemperature, then sodium triacetoxyborohydride (424 mg, 2.00 mmol, 3.00equiv) was added. The resulting solution was stirred overnight at roomtemperature and then quenched with water (10 mL), as described inExample 1, Step 6. The residue was chromatographed on a silica gelcolumn to provide 220 mg (71% yield) of t-butyl4-((3-bromo-4-(trifluoromethyl)benzyl)(methyl)amino)-4-methylpiperidine-1-carboxylateas yellow oil. LCMS (ESI, m/z): 465 [M+H]⁺.

Step 3: Preparation of t-butyl4-((3-(4-fluoropiperidin-1-yl)-4-(trifluoromethyl)benzyl)(methyl)amino)-4-methylpiperidine-1-carboxylate

A vial was charged with toluene (10 mL), t-butyl4-((3-bromo-4-(trifluoromethyl)benzyl)(methyl)amino)-4-methylpiperidine-1-carboxylate(220 mg, 0.470 mmol, 1.00 equiv), 4-fluoropiperidine (49.0 mg, 0.480mmol, 1.00 equiv), cesium carbonate (464 mg, 1.42 mmol, 3.00 equiv),palladium acetate (21.0 mg, 0.0900 mmol, 0.20 equiv), and2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (59.0 mg, 0.0900 mmol, 0.20equiv) under nitrogen. The resulting solution was stirred overnight at80° C. and then quenched with water (10 ml). The mixture was extractedwith EtOAc (3 x 10 mL) and the organic layers were combined, washed withbrine (1×10 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was chromatographed ona silica gel column to provide 135 mg (59% yield) of t-butyl4-([[3-(4-fluoropiperidin-1-yl)-4-(trifluoromethyl)phenyl]methyl](methyl)amino)-4-methylpiperidine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 488 [M+H]⁺.

Step 4: Preparation ofN-(3-(4-fluoropiperidin-1-yl)-4-(trifluoromethyl)benzyl)-N,4-dimethylpiperidin-4-amine

A vial was charged with t-butyl4-([[3-(4-fluoropiperidin-1-yl)-4-(trifluoromethyl)phenyl]methyl](methyl)amino)-4-methylpiperidine-1-carboxylate(135 mg, 0.280 mmol, 1.00 equiv), DCM (10 ml) and TFA (4 ml). Theresulting solution was stirred for 2 h at room temperature andconcentrated under reduced pressure. The mixture was diluted with water(10 mL) and the pH value of the solution was adjusted to 9 with sodiumhydroxide solution (1 mol/L aq). The mixture was extracted with DCM(3×10 mL) and the organic layers were combined, washed with brine (2×20mL), dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure as described in Example 1, Step 3 to provide 100mg (crude) ofN-(3-(4-fluoropiperidin-1-yl)-4-(trifluoromethyl)benzyl)-N,4-dimethylpiperidin-4-amineas a yellow oil. LCMS (ESI, m/z): 388 [M+H]⁺.

Step 5: Preparation of4-((3-(4-fluoropiperidin-1-yl)-4-(trifluoromethyl)benzyl)(methyl)amino)-4-methylpiperidine-1-carbonylchloride

A vial was charged withN-(3-(4-fluoropiperidin-1-yl)-4-(trifluoromethyl)benzyl)-N,4-dimethylpiperidin-4-amine(100 mg, 0.260 mmol, 1.00 equiv), DCM (10 mL) and triphosgene (38.0 mg,0.130 mmol, 0.50 equiv). DIPEA (100 mg, 0.780 mmol, 3.00 equiv) wasadded dropwise at 0° C. The resulting solution was stirred for 2 h atroom temperature and quenched by water (10 mL). The mixture wasextracted with DCM (3×10 mL) and the organic layers were combined,washed with brine (2×10 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to provide 100 mg(crude) of4-((3-(4-fluoropiperidin-1-yl)-4-(trifluoromethyl)benzyl)(methyl)amino)-4-methylpiperidine-1-carbonylchloride as a yellow oil.

Step 6: Preparation ofN-(1-(4-((3-(4-fluoropiperidin-1-yl)-4-(trifluoromethyl)benzyl)(methyl)amino)-4-methylpiperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

A vial was charged with THF (10 mL),4-((3-(4-fluoropiperidin-1-yl)-4-(trifluoromethyl)benzyl)(methyl)amino)-4-methylpiperidine-1-carbonylchloride (100 mg, 0.220 mmol, 1.00 equiv),N-(1H-pyrazol-3-yl)methanesulfonamide (36.0 mg, 0.220 mmol, 1.00 equiv),4-dimethylaminopyridine (5.00 mg, 0.0400 mmol, 0.20 equiv), and DIPEA(86.0 mg, 0.670 mmol, 3.00 equiv). The resulting solution was stirredovernight at 60° C. and diluted with water (10 mL). The mixture wasextracted with EtOAc (3×10 mL) and the organic layers were combined,washed with brine (1×10 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The crude product (150mg) was purified by preparative HPLC to provide 6.2 mg (5% yield) ofN-(1-(4-((3-(4-fluoropiperidin-1-yl)-4-(trifluoromethyl)benzyl)(methyl)amino)-4-methylpiperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamideas colorless oil. ¹H NMR (400 MHz, Chloroform-d) δ 8.04 (s, 1H), 7.56(d, J=8.1 Hz, 1H), 7.31 (s, 1H), 7.22 (d, J=8.1 Hz, 1H), 6.33 (s, 1H),4.72-4.96 (m, 1H), 3.87-4.08 (m, 2H), 3.66-3.86 (m, 2H), 3.58 (s, 2H),3.13 (s, 3H), 3.03-3.12 (m, 2H), 2.79-2.88 (m, 2H), 2.11 (s, 3H),1.93-2.08 (m, 6H), 1.48-1.70 (m, 3H), 1.07 (s, 3H). LCMS (ESI, m/z): 575[M+H]⁺.

Example 32-(2-((4-(3-acetamido-1H-pyrazole-1-carbonyl)piperazin-1-yl)methyl)-5-chlorophenoxy)aceticacid

Step 1: Preparation of t-butyl4-(3-acetamido-1H-pyrazole-1-carbonyl)piperazine-1-carboxylate

A flask was charged with N-(1H-pyrazol-3-yl)acetamide (5.00 g, 40.0mmol, 1.00 equiv), triethylamine (16.2 g, 160 mmol, 4.00 equiv) and DCM(40 mL). Then 4-nitrophenyl chloroformate (8.89 g, 44.1 mmol, 1.10equiv) was added at 0° C. The resulting solution was stirred for 2 h atroom temperature and then t-butyl piperazine-1-carboxylate (7.44 g, 40.0mmol, 1.00 equiv) was added, as described in Example 1, Step 1. Theresidue was chromatographed on a silica gel column to provide 9.00 g(67% yield) t-butyl4-(3-acetamido-1H-pyrazole-1-carbonyl)piperazine-1-carboxylate as ayellow solid. LCMS (ESI, m/z): 338 [M+H]⁺.

Step 2: Preparation ofN-(1-(piperazine-1-carbonyl)-1H-pyrazol-3-yl)acetamide

A vial was charged with t-butyl4-[(3-acetamido-1H-pyrazol-1-yl)carbonyl]piperazine-1-carboxylate (240mg, 0.720 mmol, 1.00 equiv), TFA (4 mL) and DCM (30 mL), as described inExample 1, Step 3, providing 168 mg (quantitative) ofN-(1-(piperazine-1-carbonyl)-1H-pyrazol-3-yl)acetamide as a yellowsolid. LCMS (ESI, m/z): 238 [M+H]⁺.

Step 3: Preparation of t-butyl 2-(5-chloro-2-formylphenoxy)acetate

A vial was charged with 4-chloro-2-hydroxybenzaldehyde (1.00 g, 6.39mmol, 1.00 equiv), t-butyl 2-bromoacetate (1.38 g, 7.07 mmol, 1.10equiv), potassium carbonate (1.77 g, 12.8 mmol, 2.00 equiv) and ACN (20mL). The resulting solution was stirred overnight at room temperatureand quenched by water (20 mL). The mixture was extracted with DCM (3×30mL) and the organic layers were combined, washed with water (3×10 mL),dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was chromatographed on a silica gel columnto provide 420 mg (24% yield) of t-butyl2-(5-chloro-2-formylphenoxy)acetate as a white solid. LCMS (ESI, m/z):271 [M+H]⁺.

Step 4: Preparation of t-butyl2-(2-((4-(3-acetamido-1H-pyrazole-1-carbonyl)piperazin-1-yl)methyl)-5-chlorophenoxy)acetate

A vial was charged withN-[1-[(piperazin-1-yl)carbonyl]-1H-pyrazol-3-yl]acetamide (143 mg, 0.600mmol, 1.00 equiv), t-butyl 2-(5-chloro-2-formylphenoxy)acetate (178 mg,0.660 mmol, 1.10 equiv) and DCM (15 mL). The resulting solution wasstirred for 1 h at room temperature and then sodiumtriacetoxyborohydride (255 mg, 1.20 mmol, 2.00 equiv) was added, asdescribed in Example 1, Step 6. The residue was chromatographed on asilica gel column to provide 200 mg (67% yield) of t-butyl2-(2-((4-(3-acetamido-1H-pyrazole-1-carbonyl)piperazin-1-yl)methyl)-5-chlorophenoxy)acetateas a white solid. LCMS (ESI, m/z): 492 [M+H]⁺.

Step 5: Preparation of2-(2-((4-(3-acetamido-1H-pyrazole-1-carbonyl)piperazin-1-yl)methyl)-5-chlorophenoxy)aceticacid

A vial was charged with t-butyl2-[5-chloro-2-([4-((3-acetamido-1H-pyrazol-1-yl)carbonyl]piperazin-1-yl]methyl)phenoxy]acetate(200 mg, 0.410 mmol, 1.00 equiv), TFA (2 mL) and DCM (15 mL), asdescribed in Example 1, Step 1. The crude product was purified bypreparative HPLC to provide 22.6 mg (13% yield) of2-(2-((4-(3-acetamido-1H-pyrazole-1-carbonyl)piperazin-1-yl)methyl)-5-chlorophenoxy)aceticacid as a white solid. ¹H NMR: (300 MHz, Methanol-d₄) δ 8.10 (s, 1H),7.19-7.41 (m, 2H), 7.01-7.12 (m, 1H), 6.80 (m, 1H), 4.68 (s, 2H),4.01-4.21 (m, 6H), 3.15-3.28 (m, 4H), 2.10 (s, 3H). LCMS (ESI, m/z): 436[M+H]⁺.

Example 41-(2-((4-(3-acetamido-1H-pyrazole-1-carbonyl)piperazin-1-yl)methyl)-5-chlorophenoxy)cyclopropane-1-carboxylicacid

Step 1: Preparation of methyl1-(5-chloro-2-formylphenoxy)cyclopropane-1-carboxylate

A vial was charged with methyl 1-hydroxycyclopropane-1-carboxylate (1.28g, 11.0 mmol, 1.10 equiv) and THF (20 mL). Sodium hydride (60% in oil,600 mg, 15.0 mmol, 1.50 equiv) was added dropwise at 0° C. The resultingsolution was stirred for 0.5 h at room temperature. Then4-chloro-2-fluorobenzaldehyde (1.59 g, 10.0 mmol, 1.00 equiv) was added.The resulting solution was stirred overnight at room temperature andquenched by water (20 mL). The mixture was extracted with DCM (3×30 mL)and the organic layers were combined, washed with water (3×10 mL), driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was chromatographed on a silica gel column toprovide 500 mg (20% yield) of methyl1-(5-chloro-2-formylphenoxy)cyclopropane-1-carboxylate as a white solid.LCMS (ESI, m/z): 255 [M+H]⁺.

Step 2: Preparation of t-butyl4-(4-chloro-2-(1-(methoxycarbonyl)cyclopropoxy)benzyl)piperazine-1-carboxylate

A vial was charged with t-butyl piperazine-1-carboxylate (186 mg, 1.00mmol, 1.00 equiv), methyl 1-(5-chloro-2-formylphenoxy)cyclopropane-1-carboxylate (280 mg, 1.10 mmol, 1.10 equiv) and DCM (15mL). The resulting solution was stirred for 1 h at room temperature andthen sodium triacetoxyborohydride (424 mg, 2.00 mmol, 2.00 equiv) wasadded. The resulting solution was stirred for 1 h at room temperatureand quenched by water (10 mL), as described in Example 1, Step 6. Theresidue was chromatographed on a silica gel column to provide 320 mg(75% yield) of t-butyl4-(4-chloro-2-(1-(methoxycarbonyl)cyclopropoxy)benzyl)piperazine-1-carboxylateas a white solid. LCMS (ESI, m/z): 425 [M+H]⁺.

Step 3: Preparation of1-(2-((4-(t-butoxycarbonyl)piperazin-1-yl)methyl)-5-chlorophenoxy)cyclopropane-1-carboxylicacid

A 40-mL vial was charged with t-butyl4-(4-chloro-2-(1-(methoxycarbonyl)cyclopropoxy)benzyl)piperazine-1-carboxylate(320 mg, 0.750 mmol, 1.00 equiv), lithium hydroxide (54.0 mg, 2.25 mmol,3.00 equiv), MeOH (20 mL) and water (5 mL). The resulting solution wasstirred for 2 h at room temperature and concentrated under reducedpressure. The resulting solution was quenched by water (20 mL). The pHvalue of the solution was adjusted to 5˜6 with hydrochloric acid (1M).The mixture was extracted with DCM (3×20 mL), washed with water (3×10mL), dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure, resulting in 280 mg (90% yield) of1-(2-((4-(t-butoxycarbonyl)piperazin-1-yl)methyl)-5-chlorophenoxy)cyclopropane-1-carboxylicacid as a white solid. LCMS (ESI, m/z): 411 [M+H]⁺.

Step 4: Preparation of1-(5-chloro-2-(piperazin-1-ylmethyl)phenoxy)cyclopropane-1-carboxylicacid

A vial was charged with1-(2-((4-(t-butoxycarbonyl)piperazin-1-yl)methyl)-5-chlorophenoxy)cyclopropane-1-carboxylicacid (280 mg, 0.680 mmol, 1.00 equiv), TFA (2 mL) and DCM (15 mL), asdescribed in Example 1, Step 3, resulting in 211 mg (quantitative) of1-(5-chloro-2-(piperazin-1-ylmethyl)phenoxy)cyclopropane-1-carboxylicacid as a white solid. LCMS (ESI, m/z): 311 [M+H]⁺.

Step 5: Preparation of1-(2-((4-(3-acetamido-1H-pyrazole-1-carbonyl)piperazin-1-yl)methyl)-5-chlorophenoxy)cyclopropane-1-carboxylicacid

A vial was charged with N-(1H-pyrazol-3-yl)acetamide (85.0 mg, 0.680mmol, 1.00 equiv), triphosgene (101 mg, 0.340 mmol, 0.50 equiv) and DCM(15 mL). Then DIPEA (529 mg, 4.10 mmol, 6.00 equiv) was added at 0° C.The resulting solution was stirred for 2 h at room temperature. Then1-(5-chloro-2-(piperazin-1-ylmethyl)phenoxy)cyclopropane-1-carboxylicacid (211 mg, 0.680 mmol, 1.00 equiv) was added, as described in Example2, Step 5. The crude product was purified by preparative HPLC to provide56.0 mg (18% yield) of1-(2-((4-(3-acetamido-1H-pyrazole-1-carbonyl)piperazin-1-yl)methyl)-5-chlorophenoxy)cyclopropane-1-carboxylicacid as a white solid. ¹H NMR: (300 MHz, Methanol-d₄) δ 8.08 (s, 1H),7.27-7.41 (m, 2H), 6.98-7.12 (m, 1H), 6.79 (s, 1H), 4.05 (br, 6H), 3.12(br, 4H), 2.11 (s, 3H), 1.41-1.51 (m, 2H), 1.21-1.32 (m, 2H). LCMS (ESI,m/z): 462 [M+H]⁺.

Example 5N-(1-(4-(3-(1,3,4-Oxadiazol-2-yl)-4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

Step 1: Synthesis of tert-butyl4-(3-(methoxycarbonyl)-4-(trifluoromethyl)phenoxy)piperidine-1-carboxylate

A 30-mL pressure tank reactor was charged with tent-butyl4-[3-bromo-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (1.00 g,2.36 mmol, 1.00 equiv), [1,1-is(diphenylphosphino)ferrocene]dichloropalladium(II) (173 mg, 0.236 mmol,0.10 equiv), methanol (10 mL), and triethylamine (715 mg, 7.08 mmol,3.00 equiv). Carbon monoxide was introduced, and the reaction mixturewas stirred overnight at 100° C. before quenching with water (20 mL).The resulting solution was extracted with ethyl acetate (3×20 mL) andthe organic layers were combined, washed with brine (2×20 mL), driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was chromatographed on a silica gel column toprovide 0.750 g (79% yield) of tent-butyl4-(3-(methoxycarbonyl)-4-(trifluoromethyl)phenoxy)piperidine-1-carboxylate. LCMS (ESI, m/z): 404 [M+H]⁺.

Step 2: Synthesis of tert-butyl4-(3-(hydrazinecarbonyl)-4-(trifluoromethyl)phenoxy)piperidine-1-carboxylate

A flask was charged with tert-butyl4-(3-(methoxycarbonyl)-4-(trifluoromethyl)phenoxy)piperidine-1-carboxylate(750 mg, 1.86 mmol, 1.00 equiv), methanol (30 mL), and hydrazine hydrate(465 mg, 9.29 mmol, 5.00 equiv). The reaction mixture was stirredovernight at 80° C. and quenched with water (20 mL). The resultingsolution was extracted with ethyl acetate (3×20 mL) and the organiclayers were combined, washed with brine (2×20 mL), dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was chromatographed on a silica gel to provide 573 mg (76%yield) of tert-butyl4-(3-(hydrazinecarbonyl)-4-(trifluoromethyl)phenoxy)piperidine-1-carboxylate.LCMS (ESI, m/z): 404 [M+H]⁺.

Step 3: Synthesis of tert-butyl4-(3-(1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)phenoxy)piperidine-1-carboxylate

A flask was charged with tert-butyl4-(3-(hydrazinecarbonyl)-4-(trifluoromethyl)phenoxy)piperidine-1-carboxylate (130 mg, 0.320 mmol, 1.00 equiv), dimethyl sulfoxide (10 mL), and(diethoxymethoxy)ethane (191 mg, 1.29 mmol, 4.00 equiv). The resultingsolution was stirred for 1 h at room temperature prior to addition ofboron trifluoride diethylether (55.0 mg, 0.390 mmol, 1.20 equiv). Thereaction mixture was stirred for 3 h at 80° C. and quenched with water(20 mL). The resulting solution was extracted with ethyl acetate (3×20mL) and the organic layers were combined, washed with brine (2×20 mL),dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was chromatographed on a silica gel columnto provide 40.0 mg (30% yield) of tert-butyl4-(3-(1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)phenoxy)piperidine-1-carboxylate.LCMS (ESI, m/z): 414 [M+H]⁺.

Step 4: Synthesis of2-(5-(piperidin-4-yloxy)-2-(trifluoromethyl)phenyl)-1,3,4-oxadiazole

A flask was charged with tent-butyl4-(3-(1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)phenoxy)piperidine-1-carboxylate(80.0 mg, 0.190 mmol, 1.00 equiv), dichloromethane (4 mL), andtrifluoroacetic acid (1 mL). The resulting solution was stirred for 3 hat room temperature and concentrated under reduced pressure to provide100 mg (crude) of2-(5-(piperidin-4-yloxy)-2-(trifluoromethyl)phenyl)-1,3,4-oxadiazole.LCMS (ESI, m/z): 314 [M+H]⁺.

Step 5: Synthesis ofN-(1-(4-(3-(1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

A vial was charged with 4-nitrophenyl3-methanesulfonamido-1H-pyrazole-1-carboxylate (104 mg, 0.320 mmol, 2.00equiv), dichloromethane (10 mL), and2-(5-(piperidin-4-yloxy)-2-(trifluoromethyl)phenyl)-1,3,4-oxadiazole(48.6 mg, 0.160 mmol, 1.00 equiv) under nitrogen.N,N-Diisopropylethylamine (60.0 mg, 0.470 mmol, 3.00 equiv) was addeddropwise at 0° C., and the resulting solution was stirred overnight atroom temperature and quenched with water (10 mL). The mixture wasextracted with dichloromethane (3×10 mL) and the organic layers werecombined, washed with brine (2×10 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The crudeproduct (160 mg) was purified by preparative HPLC to afford 25.8 mg (33%yield) ofN-(1-(4-(3-(1,3,4-oxadiazol-2-yl)-4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide.¹H NMR (400 MHz, Chloroform-d) δ 8.61 (s, 1H), 8.08 (d, J=2.8 Hz, 1H),7.81 (d, J=8.8 Hz, 1H), 7.60 (d, J=2.8 Hz, 1H), 7.32 (s, 1H), 7.19-7.22(m, 1H), 6.34 (d, J=2.8 Hz, 1H), 4.77-4.82 (m, 1H), 3.93-3.99 (m, 4H),3.18 (s, 3H), 2.10-2.17 (m, 2H), 1.97-2.03 (m, 2H). LCMS (ESI, m/z): 501[M+H]⁺.

Example 6N-(1-(4-(4-chloro-3-(cyclopentyloxy)phenoxy)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

Step 1: Preparation of 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate

A vial was charged with N-(1H-pyrazol-3-yl)methanesulfonamide (172 mg,1.07 mmol, 1.00 equiv) in DCM (10 mL) and 4-nitrophenyl chloroformate(237 mg, 1.18 mmol, 1.10 equiv). Triethylamine (324 mg, 3.21 mmol, 3.00equiv) was added, as described in Example 1, Step 1. The resultingsolution was stirred for 2 h at room temperature and concentrated underreduced pressure to provide 360 mg (crude) of 4-nitrophenyl3-methanesulfonamido-1H-pyrazole-1-carboxylate as a yellow oil. LCMS(ESI, m/z): 327 [M+H]⁺.

Step 2: Preparation of t-butyl4-(3-bromo-4-chlorophenoxy)piperidine-1-carboxylate

A flask was charged with t-butyl 4-hydroxypiperidine-1-carboxylate (2.88g, 14.3 mmol, 1.50 equiv), N,N-dimethylformamide (20 mL), and sodiumhydride (574 mg, 14.3 mmol, 1.50 equiv, 60% in mineral oil). Theresulting solution was stirred for 0.5 h at 0° C.2-Bromo-1-chloro-4-fluorobenzene (2.00 g, 9.55 mmol, 1.00 equiv) wasadded. The resulting solution was stirred overnight at room temperatureand quenched with water (20 mL), as described in Example 1, Step 4. Theresidue was chromatographed on a silica gel column to provide 2.62 g(70% yield) of t-butyl4-(3-bromo-4-chlorophenoxy)piperidine-1-carboxylate as yellow oil. LCMS(ESI, m/z): 390 [M+H]⁺.

Step 3: Preparation of t-butyl4-(4-chloro-3-hydroxyphenoxy)piperidine-1-carboxylate

A flask was charged with t-butyl4-(3-bromo-4-chlorophenoxy)piperidine-1-carboxylate (585 mg, 1.50 mmol,1.00 equiv), trimethyl borate (203 mg, 1.95 mmol, 1.30 equiv), and THF(10 mL) under nitrogen. The mixture was cooled to −78° C. n-Butyllithium(0.78 mL, 1.95 mmol, 1.30 equiv, 2.5 M in hexane) was added dropwise at−78° C. over 0.5 h. Acetic acid (180 mg, 3.00 mmol, 2.00 equiv) wasadded at −20° C. Hydrogen peroxide (855 mg, 7.50 mmol, 5.00 equiv, 30%in water) was added dropwise at −10° C. over 5 min. The resultingsolution was stirred for 5 h at room temperature and quenched withsaturated sodium thiosulfate solution (20 mL). The resulting mixture wasconcentrated under reduced pressure. The residue was chromatographed ona silica gel column to provide 300 mg (61% yield) of t-butyl4-(4-chloro-3-hydroxyphenoxy)piperidine-1-carboxylate as a yellow oil.LCMS (ESI, m/z): 328 [M+H]⁺.

Step 4: Preparation of t-butyl4-(4-chloro-3-(cyclopentyloxy)phenoxy)piperidine-1-carboxylate

A flask was charged with t-butyl 4-(4-chloro-3-hydroxyphenoxy)piperidine-1-carboxylate (300 mg, 0.920 mmol, 1.00 equiv),N,N-dimethylformamide (5 mL), iodocyclopentane (359 mg, 1.83 mmol, 2.00equiv), and cesium carbonate (897 mg, 2.75 mmol, 3.00 equiv). Theresulting solution was stirred for 3 h at room temperature and quenchedwith water (10 mL), as described in Example 3, Step 3. The residue waschromatographed on a silica gel column to provide 260 mg (72% yield) oft-butyl 4-(4-chloro-3-(cyclopentyloxy)phenoxy)piperidine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 396 [M+H]⁺.

Step 5: Preparation of 4-(4-chloro-3-(cyclopentyloxy)phenoxy)piperidine

A flask was charged with t-butyl4-(4-chloro-3-(cyclopentyloxy)phenoxy)piperidine-1-carboxylate (260 mg,0.660 mmol, 1.00 equiv), DCM (10 mL), and TFA (2 mL), as described inExample 1, Step 3, to provide 294 mg (crude) of4-(4-chloro-3-(cyclopentyloxy)phenoxy)piperidine as a yellow oil. LCMS(ESI, m/z): 296 [M+H]⁺.

Step 6: Preparation ofN-(1-(4-(4-chloro-3-(cyclopentyloxy)phenoxy)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

A vial was charged with 4-nitrophenyl3-methanesulfonamido-1H-pyrazole-1-carboxylate (430 mg, 1.32 mmol, 2.00equiv), 4-(4-chloro-3-(cyclopentyloxy)phenoxy)piperidine (194 mg, 0.658mmol, 1.00 equiv), and DCM (10 mL) under nitrogen. DIPEA (255 mg, 1.98mmol, 3.00 equiv) was added dropwise at 0° C. The resulting solution wasstirred for 3 h at room temperature and quenched with water (10 mL). Themixture was extracted with DCM (3×10 mL) and the organic layers werecombined, washed with brine (2×10 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The crudeproduct (250 mg) was purified by preparative HPLC to provide 88.2 mg(28% yield) ofN-(1-(4-(4-chloro-3-(cyclopentyloxy)phenoxy)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamideas a white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.08 (d, J=2.8 Hz,1H), 7.25 (d, J=8.8 Hz, 1H), 7.16 (s, 1H), 6.54 (d, J=2.4 Hz, 1H),6.43-6.46 (m, 1H), 6.34 (d, J=2.8 Hz, 1H), 4.77-4.80 (m, 1H), 4.56-4.59(m, 1H), 3.85-3.97 (m, 4H), 3.17 (s, 3H), 2.02-2.10 (m, 2H), 1.85-1.99(m, 8H), 1.64-1.67 (m, 2H). LCMS (ESI, m/z): 505 [M+Na]⁺.

Example 7N-(1-(4-(2-(1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

Step 1: Preparation of 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate

A vial was charged with N-(1H-pyrazol-3-yl)methanesulfonamide (172 mg,1.07 mmol, 1.00 equiv) in DCM (10 mL) and 4-nitrophenyl chloroformate(237 mg, 1.18 mmol, 1.10 equiv). Triethylamine (324 mg, 3.21 mmol, 3.00equiv) was added, as described in Example 1, Step 1 to provide 360 mg(crude) of 4-nitrophenyl 3-(methylsulfonamido)-1H-pyrazole-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 327 [M+H]⁺.

Step 2: Preparation of t-butyl4-(2-bromo-3-(trifluoromethyl)phenoxy)piperidine-1-carboxylate

A flask was charged with t-butyl 4-hydroxypiperidine-1-carboxylate (1.24g, 6.16 mmol, 1.50 equiv) and N,N-dimethylformamide (20 mL). Theresulting solution was stirred for 0.5 h at 0° C. Sodium hydride (247mg, 6.16 mmol, 1.50 equiv, 60% in mineral oil) was added. The resultingsolution was stirred for 0.5 h at 0° C.2-Bromo-1-fluoro-3-(trifluoromethyl)benzene (1.00 g, 4.12 mmol, 1.00equiv) was added, as described in Example 4, Step 1. The residue waschromatographed on a silica gel column to provide 1.30 g (74% yield) oft-butyl 4-(2-bromo-3-(trifluoromethyl)phenoxy)piperidine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 424 [M+H]⁺.

Step 3: Preparation of t-butyl4-(2-(methoxycarbonyl)-3-(trifluoromethyl)phenoxy)piperidine-1-carboxylate

A flask was charged with t-butyl4-(2-bromo-3-(trifluoromethyl)phenoxy)piperidine-1-carboxylate (1.80 g,4.18 mmol, 1.00 equiv) under nitrogen. THF (10 mL) was added.n-Butyllithium (2 mL, 5.02 mmol, 1.20 equiv, 2.5 M in n-hexane) wasadded dropwise at −78° C. The mixture was stirred for 15 min at −78° C.Chloro(methoxy)methanone (1.19 g, 12.6 mmol, 3.00 equiv) was added. Theresulting solution was stirred for 2 h at room temperature and quenchedwith water (10 mL). The resulting solution was extracted with EtOAc(3×20 mL) and the organic layers were combined, washed with brine (2×20mL), dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was chromatographed on a silica gelcolumn to provide 0.180 g (11% yield) of t-butyl4-(2-(methoxycarbonyl)-3-(trifluoromethyl)phenoxy)piperidine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 404 [M+H]⁺.

Step 4: Preparation of t-butyl4-(2-(hydrazinecarbonyl)-3-(trifluoromethyl)phenoxy)piperidine-1-carboxylate

A flask was charged with t-butyl4-(2-(methoxycarbonyl)-3-(trifluoromethyl)phenoxy)piperidine-1-carboxylate(300 mg, 0.740 mmol, 1.00 equiv), hydrazine hydrate (247 mg, 3.70 mmol,5.00 equiv, 80% in water), and MeOH (40 mL). The resulting solution wasstirred overnight at 80° C. and quenched with water (10 mL), asdescribed in Example 5, Step 4. The residue was chromatographed on asilica gel column to provide 199 mg (66% yield) of t-butyl4-(2-(hydrazinecarbonyl)-3-(trifluoromethyl)phenoxy)piperidine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 404 [M+H]⁺.

Step 5: Preparation of t-butyl4-(2-(1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)phenoxy)piperidine-1-carboxylate

A flask was charged with t-butyl4-(2-(hydrazinecarbonyl)-3-(trifluoromethyl)phenoxy)piperidine-1-carboxylate(199 mg, 0.490 mmol, 1.00 equiv), DMSO (10 mL), and(diethoxymethoxy)ethane (293 mg, 1.98 mmol, 4.00 equiv). The resultingsolution was stirred 1 h at room temperature. Boron trifluoride etherate(84.2 mg, 0.588 mmol, 1.20 equiv) was added. The resulting solution wasstirred for 3 h at 80° C. and quenched with water (10 mL), as describedin Example 5, Step 5. The residue was chromatographed on a silica gelcolumn to provide 33.0 mg (16% yield) of t-butyl4-(2-(1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)phenoxy)piperidine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 414 [M+H]⁺.

Step 6: Preparation of2-(2-(piperidin-4-yloxy)-6-(trifluoromethyl)phenyl)-1,3,4-oxadiazole

A flask was charged with t-butyl4-(2-(1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)phenoxy)piperidine-1-carboxylate(33.0 mg, 0.0800 mmol, 1.00 equiv), DCM (4 mL), and TFA (1 mL), asdescribed in Example 1, Step 3 to provide 30.0 mg (crude) of2-(2-(piperidin-4-yloxy)-6-(trifluoromethyl)phenyl)-1,3,4-oxadiazole asa red oil. LCMS (ESI, m/z): 314 [M+H]⁺.

Step 7: Preparation ofN-(1-(4-(2-(1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

A vial was charged with2-(2-(piperidin-4-yloxy)-6-(trifluoromethyl)phenyl)-1,3,4-oxadiazole(20.0 mg, 0.0639 mmol, 1.00 equiv), 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate (52.2 mg, 0.160 mmol,2.50 equiv), and DCM (5 mL) under nitrogen. DIPEA (24.8 mg,0.192 mmol,3.00 equiv) was added dropwise at 0° C. The resulting solution wasstirred for 5 h at room temperature and quenched with water (5 mL), asdescribed in Example 2, Step 6. The crude product (200 mg) was purifiedby preparative HPLC to provide 10.5 mg (33% yield) ofN-(1-(4-(2-(1,3,4-oxadiazol-2-yl)-3-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamideas a white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.60 (s, 1H), 8.14(d, J=8.0 Hz, 1H), 8.08 (d, J=2.4 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.31(s, 1H), 6.36 (d, J=2.4 Hz, 1H), 4.97 (br, 1H) 4.10-4.13 (m, 2H),3.91-3.93 (m, 2H), 3.16 (s, 3H), 2.03-2.16 (m, 4H). LCMS (ESI, m/z): 501[M+H]⁺.

Example 8N-(1-(4-(4-chloro-3-(7-oxa-2-azaspiro[3.5]nonan-2-yl)benzyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

Step 1: Preparation of t-butyl4-(3-bromo-4-chlorobenzyl)piperazine-1-carboxylate

A flask was charged with 3-bromo-4-chlorobenzaldehyde (1.00 g, 4.56mmol, 1.00 equiv), t-butyl piperazine-1-carboxylate (1.02 g, 5.48 mmol,1.20 equiv), triethylamine (1.38 g, 13.7 mmol, 3.00 equiv), and DCE (10mL). The mixture was stirred for 30 min at room temperature. Sodiumtriacetoxyborohydride (2.90 g, 13.7 mmol, 3.00 equiv) was added. Theresulting solution was stirred overnight at room temperature andquenched with water (10 mL), as described in Example 1, Step 6. Theresidue was chromatographed on a silica gel column to provide 1.50 g(84% yield) of t-butyl4-(3-bromo-4-chlorobenzyl)piperazine-1-carboxylate as a white oil. LCMS(ESI, m/z): 389 [M+H]⁺.

Step 2: Preparation of t-butyl4-(4-chloro-3-(7-oxa-2-azaspiro[3.5]nonan-2-yl)benzyl)piperazine-1-carboxylate

A flask was charged with t-butyl4-(3-bromo-4-chlorobenzyl)piperazine-1-carboxylate (200 mg, 0.513 mmol,1.00 equiv), 7-oxa-2-azaspiro[3.5]nonane (78.2 mg, 0.616 mmol, 1.20equiv), tris(dibenzylideneacetone)dipalladium (23.5 mg, 0.0256 mmol,0.05 equiv), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine(47.9 mg, 0.102 mmol, 0.20 equiv), cesium carbonate (502 mg, 1.54 mmol,3.00 equiv), and toluene (5 mL). The resulting solution was stirredovernight at 90° C. and quenched with water (5 mL). The resultingsolution was extracted with DCM (3×20 mL) and the organic layers werecombined, washed with brine (2×5 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas chromatographed on a silica gel column to provide 105 mg (47% yield)of t-butyl4-(4-chloro-3-(7-oxa-2-azaspiro[3.5]nonan-2-yl)benzyl)piperazine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 436 [M+H]⁺.

Step 3: Preparation of2-(2-chloro-5-(piperazin-1-ylmethyl)phenyl)-7-oxa-2-azaspiro[3.5]nonane

A flask was charged with t-butyl4-(4-chloro-3-(7-oxa-2-azaspiro[3.5]nonan-2-yl)benzyl)piperazine-1-carboxylate(105 mg, 0.241 mmol, 1.00 equiv), DCM (4 mL), and TFA (1 mL), asdescribed in Example 1, Step 3 to provide 100 mg (crude) of2-(2-chloro-5-(piperazin-1-ylmethyl)phenyl)-7-oxa-2-azaspiro[3.5]nonaneas a yellow oil. LCMS (ESI, m/z): 336 [M+H]⁺.

Step 4: Preparation ofN-(1-(4-(4-chloro-3-(7-oxa-2-azaspiro[3.5]nonan-2-yl)benzyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

A flask was charged with 4-nitrophenylchloroformate (114 mg, 0.564 mmol,2.10 equiv), DCM (5 mL), and N-(1H-pyrazol-3-yl)methanesulfonamide (86.2mg, 0.535 mmol, 2.00 equiv). Triethylamine (108 mg, 1.07 mmol, 4.00equiv) was added dropwise at 0° C. The mixture was stirred for 2 h atroom temperature.2-(2-Chloro-5-(piperazin-1-ylmethyl)phenyl)-7-oxa-2-azaspiro[3.5]nonane(90.0 mg, 0.268 mmol, 1.00 equiv) was added. The resulting solution wasstirred for 2 h at room temperature and quenched with water (5 mL), asdescribed in Example 1, Step 1. The crude product (140 mg) was purifiedby preparative HPLC to provide 56.0 mg (40% yield) ofN-(1-(4-(4-chloro-3-(7-oxa-2-azaspiro[3.5]nonan-2-yl)benzyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide as awhite solid. ¹H NMR (300 MHz, Chloroform-d) δ 8.04 (d, J=3.0 Hz, 1H),7.15 (d, J=8.1 Hz, 1H), 6.65-6.68 (m, 1H), 6.50 (br, 1H), 6.31 (d, J=3.0Hz, 1H), 3.86-3.89 (m, 8H), 3.66-3.70 (m, 4H), 3.50 (br, 2H), 3.13 (s,3H), 2.56 (br, 4H), 1.83-1.86 (m, 4H). LCMS (ESI, m/z): 523 [M+H]⁺.

Example 95-(2-Chloro-5-((4-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)piperazin-1-yl)methyl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide

Step 1: Preparation of t-butyl5-(2-chloro-5-formylphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

A flask was charged with 3-bromo-4-chlorobenzaldehyde (4.00 g, 18.2mmol, 1.00 equiv), t-butyl octahydropyrrolo[3,4-c]pyrrole-2-carboxylate(5.83 g, 27.5 mmol, 1.50 equiv), tris(dibenzylideneacetone)dipalladium(838 mg, 0.920 mmol, 0.05 equiv),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.71 g, 2.75 mmol, 0.15equiv), cesium carbonate (17.9 g, 54.9 mmol, 3.00 equiv), and toluene(50 mL). The resulting solution was stirred overnight at 90° C. andquenched with water (100 mL). The resulting solution was extracted withEtOAc (3×100 mL) and the organic layers were combined, washed with brine(2×100 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was chromatographed ona silica gel column to provide 5.00 g (78% yield) of t-butyl5-(2-chloro-5-formylphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylateas a yellow oil. LCMS (ESI, m/z): 351 [M+H]⁺.

Step 2: Preparation of t-butyl5-(2-chloro-5-((4-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)piperazin-1-yl)methyl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

A flask was charged with t-butyl5-(2-chloro-5-formylphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(1.40 g, 3.99 mmol, 1.00 equiv), DCE (20 mL),N-[1-[(piperazin-1-yl)carbonyl]-1H-pyrazol-3-yl]methanesulfonamide (1.42g, 5.20 mmol, 1.30 equiv), and triethylamine (1.21 g, 11.9 mmol, 3.00equiv). The resulting solution was stirred for 1 h at room temperature.Sodium triacetoxyborohydride (2.54 g, 12.0 mmol, 3.00 equiv) was added.The resulting solution was stirred overnight at room temperature andquenched with water (20 mL), as described in Example 1, Step 6. Theresidue was chromatographed on a silica gel column to provide 1.73 g(71% yield) of t-butyl5-(2-chloro-5-((4-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)piperazin-1-yl)methyl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylateas a yellow oil. LCMS (ESI, m/z): 608 [M+H]⁺.

Step 3: Preparation ofN-(1-(4-(4-chloro-3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

A flask was charged with t-butyl5-(2-chloro-5-((4-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)piperazin-1-yl)methyl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(250 mg, 0.410 mmol, 1.00 equiv), DCM (5 mL), and TFA (1 mL). Theresulting solution was stirred for 2 h at room temperature andconcentrated under reduced pressure. The mixture was dissolved insaturated NaHCO₃ solution (10 mL), as described in Example 1, Step 3.The crude product (200 mg) was purified by preparative HPLC to provide57.0 mg (27% yield) ofN-(1-(4-(4-chloro-3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamideas a white solid. LCMS (ESI, m/z): 508 [M+H]⁺.

Step 4: Preparation of5-(2-chloro-5-((4-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)piperazin-1-yl)methyl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamide

A 50-mL round-bottom flask was charged withN-(1-(4-(4-chloro-3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide(167 mg, 0.329 mmol, 1.00 equiv), DCM (5 mL), andisocyanatotrimethylsilane (75.7 mg, 0.658 mmol, 2.00 equiv). Theresulting solution was stirred overnight at room temperature andconcentrated under reduced pressure. The crude product (200 mg) waspurified by preparative HPLC to provide 36.0 mg (20% yield) of5-(2-chloro-5-((4-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)piperazin-1-yl)methyl)phenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxamideas a white solid. ¹H NMR (300 MHz, Methanol-d₄) δ 8.25 (br, 1H), 8.02(d, J=2.7 Hz, 1H), 7.25 (s, 1H), 6.91 (br, 1H), 6.80-6.83 (m, 1H), 6.33(d, J=2.7 Hz, 1H), 4.54 (br, 2H), 3.84 (br, 4H), 3.51-3.70 (m, 6H),3.36-3.41 (m, 2H), 3.25-3.28 (m, 2H), 3.12 (s, 3H), 3.04 (br, 2H), 2.54(br, 4H). LCMS (ESI, m/z): 551 [M+H]⁺.

Example 104-04-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)piperazin-1-yl)methyl)-2-(trifluoromethyl)benzamide

Step 1: Preparation of 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate

A flask was charged with N-(1H-pyrazol-3-yl)methanesulfonamide (161 mg,1.00 mmol, 1.00 equiv), DCM (10 mL), triethylamine (404 mg, 3.99 mmol,4.00 equiv), and 4-nitrophenyl chloroformate (241 mg, 1.20 mmol, 1.20equiv), as described in Example 1, Step 1 to provide 326 mg (crude) of4-nitrophenyl 3-(methylsulfonamido)-1H-pyrazole-1-carboxylate as ayellow powder. LCMS (ESI, m/z): 327 [M+H]⁺.

Step 2: Preparation of methyl 4-formyl-2-(trifluoromethyl)benzoate

A flask was charged with 4-bromo-3-(trifluoromethyl)benzaldehyde (1.61g, 6.36 mmol, 1.00 equiv), 1,1′-bis(diphenylphosphino)ferrocenepalladiumdichloride (0.466 g, 0.636 mmol, 0.10 equiv), triethylamine (1.93 g,19.1 mmol, 3.00 equiv), and MeOH (15 mL). Carbon monoxide (10 atm) wasintroduced in. The resulting solution was stirred overnight at 80° C.and then quenched with water (30 mL), as described in Example 5, Step 3.The residue was chromatographed on a silica gel column to provide 1.00 g(68% yield) of methyl 4-formyl-2-(trifluoromethyl)benzoate as a yellowoil. ¹H NMR (400 MHz, Chloroform-d) δ10.4 (s, 1H), 8.28 (s, 1H), 8.15(d, J=8.0 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 4.00 (s, 3H).

Step 3: Preparation of t-butyl4-(4-(methoxycarbonyl)-3-(trifluoromethyl)benzyl)piperazine-1-carboxylate

A flask was charged with methyl 4-formyl-2-(trifluoromethyl)benzoate(0.800 g, 3.45 mmol, 1.00 equiv), t-butyl piperazine-1-carboxylate(0.962 g, 5.17 mmol, 1.50 equiv), and DCM (15 mL). The mixture wasstirred for 2 h at room temperature. Sodium triacetoxyborohydride (2.93g, 13.8 mmol, 4.00 equiv) was added. The resulting solution was stirredovernight at room temperature and then quenched with water (30 mL), asdescribed in Example 1, Step 6. The residue was chromatographed on asilica gel column to provide 1.26 g (91% yield) of t-butyl4-(4-(methoxycarbonyl)-3-(trifluoromethyl)benzyl)piperazine-1-carboxylateas yellow oil. LCMS (ESI, m/z): 403 [M+H]⁺.

Step 4: Preparation of4-((4-(t-butoxycarbonyl)piperazin-1-yl)methyl)-2-(trifluoromethyl)benzoicacid

A flask was charged with t-butyl4-(4-(methoxycarbonyl)-3-(trifluoromethyl)benzyl)piperazine-1-carboxylate(1.21 g, 3.01 mmol, 1.00 equiv), THF (10 mL), water (2 mL), and sodiumhydroxide (2.41 g, 60.2 mmol, 20.00 equiv). The resulting solution wasstirred overnight at 60° C. The pH of the solution was adjusted to 6with hydrochloric acid (1M). The resulting solution was extracted withDCM (3×80 mL) and the organic layers were combined, washed with brine(100 mL), dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to provide 1.40 g (crude) of4-((4-(t-butoxycarbonyl)piperazin-1-yl)methyl)-2-(trifluoromethyl)benzoicacid as a white solid. LCMS (ESI, m/z): 389 [M+H]⁺.

Step 5: Preparation of t-butyl4-(4-carbamoyl-3-(trifluoromethyl)benzyl)piperazine-1-carboxylate

A flask was charged with4-((4-(t-butoxycarbonyl)piperazin-1-yl)methyl)-2-(trifluoromethyl)benzoicacid (1.24 g, 3.19 mmol, 1.00 equiv), HATU (2.43 g, 6.39 mmol, 2.00equiv), DIPEA (1.24 g, 12.8 mmol, 4.00 equiv), N,N-dimethylformamide (10mL), and ammonia (0.5 M in 1,4-dioxane solution, 63.8 ml, 31.9 mmol,10.00 equiv). The resulting solution was stirred overnight at roomtemperature and then concentrated under reduced pressure. The residuewas chromatographed on a silica gel column to provide 1.00 g (81% yield)of t-butyl4-(4-carbamoyl-3-(trifluoromethyl)benzyl)piperazine-1-carboxyl ate as awhite solid. LCMS (ESI, m/z): 388 [M+H]⁺.

Step 6: Preparation of4-(piperazin-1-ylmethyl)-2-(trifluoromethyl)benzamide

A flask was charged with t-butyl4-[[4-carbamoyl-3-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate(520 mg, 1.34 mmol, 1.00 equiv), DCM (10 mL), and TFA (3 mL), asdescribed in Example 1, Step 3. The resulting solution was stirred for 2h at room temperature and concentrated under reduced pressure to provide550 mg (crude) of 4-(piperazin-1-ylmethyl)-2-(trifluoromethyl)benzamideas a yellow oil. LCMS (ESI, m/z): 288 [M+H]⁺.

Step 7: Preparation of4-((4-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)piperazin-1-yl)methyl)-2-(trifluoromethyl)benzamide

A flask was charged with4-(piperazin-1-ylmethyl)-2-(trifluoromethyl)benzamide (185 mg, 0.645mmol, 1.00 equiv), 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate (316 mg, 0.968 mmol,1.50 equiv), DCM (10 mL), and triethylamine (261 mg, 2.58 mmol, 4.00equiv), as described in Example 1, Step 1. The crude product (280 mg)was purified by preparative HPLC to provide 86.9 mg (28% yield) of4-((4-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)piperazin-1-yl)methyl)-2-(trifluoromethyl)benzamideas a white solid. ¹H NMR (300 MHz, Chloroform-d) δ 8.04 (d, J=2.8 Hz,1H), 7.70 (s, 1H), 7.59-7.61 (m, 2H), 7.17 (br, 1H), 6.31 (d, J=2.8 Hz,1H), 5.94 (br, 1H), 5.83 (br, 1H), 3.86 (br, 4H), 3.62 (s, 2H), 3.14 (s,3H), 2.52-2.56 (m, 4H). LCMS (ESI, m/z): 475 [M+H]⁺.

Example 11(S)-N-(1-(4-(1-(4-chloro-3-(4-fluoropiperidin-1-yl)phenyl)ethyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

Step 1: Preparation of 1-(3-bromo-4-chlorophenyl)ethan-1-ol

A vial was charged with 1-(3-bromo-4-chlorophenyl)ethan-1-one (1.00 g,4.28 mmol, 1.00 equiv) and MeOH (20 mL). Sodium borohydride (0.325 g,8.56 mmol, 2.00 equiv) was added at 0° C. The resulting solution wasstirred for 2 h at room temperature and quenched by water (10 mL), asdescribed in Example 1, Step 4 to provide 0.930 g (quantitative) of1-(3-bromo-4-chlorophenyl)ethan-1-ol as a yellow oil. LCMS (ESI, m/z):235[M+H]⁺.

Step 2: Preparation of 2-bromo-4-(1-bromoethyl)-1-chlorobenzene

A flask was charged with 1-(3-bromo-4-chlorophenyl)ethan-1-ol (0.900 g,3.81 mmol, 1.00 equiv) and DCM (20 mL). Tribromophosphane (10.3 g, 38.1mmol, 10.0 equiv) was added dropwise at 0° C. under nitrogen atmosphere.The resulting solution was stirred for 2 h at room temperature andquenched by saturated NaHCO₃ solution (50 mL). The mixture was extractedwith EtOAc (3×50 mL) and the organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was chromatographed on a silica gel column toprovide 0.827 g (72% yield) of 2-bromo-4-(1-bromoethyl)-1-chlorobenzeneas a yellow oil.

Step 3: Preparation of t-butyl4-(1-(3-bromo-4-chlorophenyl)ethyl)piperazine-1-carboxylate

A 40-mL vial was charged with 2-bromo-4-(1-bromoethyl)-1-chlorobenzene(0.827 g, 2.77 mmol, 1.00 equiv) and N,N-dimethylformamide (20 mL). Thensodium hydride (60% in oil, 0.556 g, 13.9 mmol, 3.00 equiv) was added at0° C. and stirred for 0.5 h at room temperature. Then t-butylpiperazine-1-carboxylate (1.03 g, 5.53 mmol, 2.00 equiv) was added. Theresulting solution was stirred overnight at room temperature andquenched by water (10 mL), as described in Example 4, Step 1. Theresidue was chromatographed on a silica gel column to provide 0.950 g(85% yield) of t-butyl4-(1-(3-bromo-4-chlorophenyl)ethyl)piperazine-1-carboxyl ate as a yellowoil. LCMS (ESI, m/z): 403 [M+H]⁺.

Step 4: Preparation of t-butyl4-(1-(4-chloro-3-(4-fluoropiperidin-1-yl)phenyl)ethyl)piperazine-1-carboxylate

A 40-mL vial was charged with t-butyl4-[1-(3-bromo-4-chlorophenyl)ethyl]piperazine-1-carboxylate (590 mg,1.46 mmol, 1.00 equiv), 4-fluoropiperidine (304 mg, 2.19 mmol, 1.50equiv), cesium carbonate (1430 mg, 4.38 mmol, 3.00 equiv) and toluene(20 mL). Tris(dibenylideneacetone)dipalladium (75.6 mg, 0.0730 mmol,0.05 equiv) and racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (684mg, 1.10 mmol, 0.75 equiv) were added under nitrogen atmosphere. Theresulting solution was stirred overnight at 80° C. and quenched by water(10 mL), as described in Example 9, Step 1. The residue waschromatographed on a silica gel column to provide 453 mg (73% yield) oft-butyl4-(1-(4-chloro-3-(4-fluoropiperidin-1-yl)phenyl)ethyl)piperazine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 426[M+H]⁺.

Step 5: Preparation of1-(1-(4-chloro-3-(4-fluoropiperidin-1-yl)phenyl)ethyl)piperazine

A flask was charged with t-butyl4-(1-(4-chloro-3-(4-fluoropiperidin-1-yl)phenyl)ethyl)piperazine-1-carboxylate(453 mg, 1.06 mmol, 1.00 equiv), concentrated HCl (2 mL) and DCM (10mL). The resulting solution was stirred for 2 h at room temperature andconcentrated under reduced pressure to provide 345 mg (quantitative) of1-(1-(4-chloro-3-(4-fluoropiperidin-1-yl)phenyl)ethyl)piperazine as awhite solid. LCMS (ESI, m/z): 326[M+H]⁺.

Step 6: Preparation of 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate

A 40-mL vial was charged with N-(1H-pyrazol-3-yl)methanesulfonamide (273mg, 1.69 mmol, 1.00 equiv), triethylamine (428 mg, 4.23 mmol, 3.00equiv) and DCM (15 mL). 4-Nitrophenyl chloroformate (279 mg, 1.38 mmol,1.00 equiv) was added dropwise at 0° C., as described in Example 1, Step1 to provide 450 mg (quantitative) of 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate as a yellow solid. LCMS(ESI, m/z): 327[M+H]⁺.

Step 7: Preparation ofN-(1-(4-(1-(4-chloro-3-(4-fluoropiperidin-1-yl)phenyl)ethyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

A flask was charged with1-(1-(4-chloro-3-(4-fluoropiperidin-1-yl)phenyl)ethyl)piperazine (345mg, 1.06 mmol, 1.00 equiv), 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate (450 mg, 1.38 mmol, 1.30equiv), triethylamine (535 mg, 5.29 mmol, 5.00 equiv) and DCM (15 mL).The resulting solution was stirred overnight at room temperature andquenched by water (10 mL), as described in Example 1, Step 1. Theresidue was chromatographed on a silica gel column to provide crudeproduct. The crude product was purified by preparative HPLC to provide195 mg (36% yield) ofN-(1-(4-(1-(4-chloro-3-(4-fluoropiperidin-1-yl)phenyl)ethyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamideas a white solid. LCMS (ESI, m/z): 513 [M+H]⁺.

Step 8: Preparation of(S)-N-(1-(4-(1-(4-chloro-3-(4-fluoropiperidin-1-yl)phenyl)ethyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

N-(1-(4-(1-(4-chloro-3-(4-fluoropiperidin-1-yl)phenyl)ethyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide(195 mg, 0.380 mmol, 1.00 equiv) was separated by chiral HPLC. ChiralHPLC separation resulted in 53.8 mg (55% yield) of(S)-N-(1-(4-(1-(4-chloro-3-(4-fluoropiperidin-1-yl)phenyl)ethyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamideas a white solid. ¹H NMR (300 MHz, Methanol-d₄) δ 7.97-8.09 (d, J=2.7Hz, 1H), 7.27-7.39 (d, J=8.1 Hz, 1H), 7.08-7.18 (d, J=1.8 Hz, 1H),6.92-7.05 (d, J=8.1 Hz, 1H), 6.17-6.31 (d, J=2.7 Hz, 1H), 4.67-4.95 (m,1H), 3.70-3.90 (br, 4H), 3.43-3.57 (m, 1H), 3.05-3.23 (m, 5H), 2.92-3.03(m, 2H), 2.58-2.72 (m, 2H), 2.41-2.58 (m, 2H), 1.89-2.20 (m, 4H),1.33-1.48 (d, J=6.9 Hz, 3H). LCMS (ESI, m/z): 513 [M+H]⁺.

Example 12N-(1-(4-(4-chloro-3-(4-azaspiro[2.4]heptan-4-yl)benzyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

Step 1: Preparation of 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate

A flask was charged with N-(1H-pyrazol-3-yl)methanesulfonamide (322 mg,2.00 mmol, 1.00 equiv), DCM (10 mL) and triethylamine (606 mg, 5.99mmol, 3.00 equiv). 4-Nitrophenyl chloroformate (485 mg, 2.41 mmol, 1.20equiv) was added at 0° C., as described in Example 1, Step 1 to provide635 mg (crude) of 4-nitrophenyl3-methanesulfonamido-1H-pyrazole-1-carboxylate as a yellow solid. LCMS(ESI, m/z): 327 [M+H]⁺.

Step 2: Preparation of t-butyl4-(3-bromo-4-chlorobenzyl)piperazine-1-carboxylate

A flask was charged with 3-bromo-4-chlorobenzaldehyde (4.38 g, 20.0mmol, 1.00 equiv), t-butyl piperazine-1-carboxylate (4.09 g, 22.0 mmol,1.10 equiv) and DCE (15 mL). After stirring at room temperature for 1 h,sodium triacetoxyborohydride (8.48 g, 40.01 mmol, 2.00 equiv) was added.The resulting solution was stirred overnight at room temperature andquenched by water (10 mL), as described in Example 1, Step 6. Theresidue was chromatographed on a silica gel column to provide 3.9 g (50%yield) of t-butyl 4-(3-bromo-4-chlorobenzyl)piperazine-1-carboxylate asa white solid. LCMS (ESI, m/z): 389 [M+H]⁺.

Step 3: Preparation of t-butyl4-(4-chloro-3-(2-oxopyrrolidin-1-yl)benzyl)piperazine-1-carboxylate

A 50-mL round-bottom flask was charged with t-butyl4-[(3-bromo-4-chlorophenyl)methyl]piperazine-1-carboxylate (500 mg, 1.28mmol, 1.00 equiv), pyrrolidin-2-one (163 mg, 1.92 mmol, 1.50 equiv),toluene (10 mL), potassium carbonate (530 mg, 3.83 mmol, 3.00 equiv),cuprous iodide (24.3 mg, 0.130 mmol, 0.10 equiv) andN,N′-dimethylethanediamine (22.5 mg, 0.262 mmol, 0.20 equiv). Theresulting solution was stirred overnight at 100° C. under nitrogenatmosphere and quenched by water (30 mL). The mixture was extracted withEtOAc (3×50 mL) and the organic layers were combined, washed with water(3×20 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was chromatographed ona silica gel column to provide 333 mg (66% yield) of t-butyl4-(4-chloro-3-(2-oxopyrrolidin-1-yl)benzyl)piperazine-1-carboxylate as ayellow oil. LCMS (ESI, m/z): 394 [M+H]⁺.

Step 4: Preparation of t-butyl4-(4-chloro-3-(4-azaspiro[2.4]heptan-4-yl)benzyl)piperazine-1-carboxylate

A flask was charged with t-butyl4-(4-chloro-3-(2-oxopyrrolidin-1-yl)benzyl)piperazine-1-carboxylate (333mg, 0.852 mmol, 1.00 equiv) and THF (5 mL). Ethylmagnesium bromide (3.0mol/L in ether, 0.56 mL, 1.70 mmol, 2.00 equiv) and methyltitaniumtriisopropoxide (1.0 mol/L in THF, 1.27 mL, 1.27 mmol, 1.50 equiv) wasadded. The resulting solution was stirred for 48 h at room temperatureunder nitrogen atmosphere and quenched by water (30 mL). The mixture wasextracted with EtOAc (3×50 mL) and the organic layers were combined,washed with water (3×20 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waschromatographed on a silica gel column to provide 175 mg (51% yield) oft-butyl4-(4-chloro-3-(4-azaspiro[2.4]heptan-4-yl)benzyl)piperazine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 406 [M+H]⁺.

Step 5: Preparation of4-(2-chloro-5-(piperazin-1-ylmethyl)phenyl)-4-azaspiro[2.4]heptane

A flask was charged with t-butyl4-(4-chloro-3-(4-azaspiro[2.4]heptan-4-yl)benzyl)piperazine-1-carboxylate(175 mg, 0.431 mmol, 1.00 equiv), DCM (10 mL) and TFA (1 mL), asdescribed in Example 1, Step 3 to provide 130 mg (quantitative) of4-(2-chloro-5-(piperazin-1-ylmethyl)phenyl)-4-azaspiro[2.4]heptane as ayellow oil. LCMS (ESI, m/z): 306 [M+H]⁺.

Step 6: Preparation ofN-(1-(4-(4-chloro-3-(4-azaspiro[2.4]heptan-4-yl)benzyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

A 50-mL round-bottom flask was charged with4-(2-chloro-5-(piperazin-1-ylmethyl)phenyl)-4-azaspiro[2.4]heptane (130mg, 0.425 mmol, 1.00 equiv), DCM (20 mL), 4-nitrophenyl3-methanesulfonamido-1H-pyrazole-1-carboxylate (163 mg, 0.510 mmol, 1.20equiv) and triethylamine (85.9 mg, 0.850 mmol, 2.00 equiv). Theresulting solution was stirred overnight at room temperature andquenched by water (10 mL), as described in Example 1, Step 1. The crudeproduct was purified by preparative HPLC to provide 35.9 mg (17% yield)ofN-(1-(4-(4-chloro-3-(4-azaspiro[2.4]heptan-4-yl)benzyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamideas a light yellow solid. ¹H NMR: (400 MHz, Methanol-d₄) δ 8.00-8.10 (s,1H), 7.30-7.39 (d, J=1.7 Hz, 1H), 7.20-7.30 (m, 1H), 6.85-6.96 (d, J=2.8Hz, 1H), 6.20-6.30 (m, 1H), 3.78-4.00 (m, 4H), 3.55 (m, 2H), 3.40-3.49(m, 2H), 3.13 (s, 3H), 2.48-2.68 (m, 4H), 1.84-2.08 (m, 4H), 0.77-0.87(m, 2H), 0.68-0.77 (m, 2H). LCMS (ESI, m/z): 493 [M+H]⁺.

Example 13N-(1-(1-((5,7-dichloro-1H-indol-2-yl)methyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazol-3-yl)acetamide

Step 1: Preparation of t-butyl8-(3-acetamido-1H-pyrazole-1-carbonyl)-1,8-diazaspiro[4.5]decane-1-carboxylate

A flask was charged with N-(1H-pyrazol-3-yl)acetamide (1.00 g, 7.99mmol, 1.00 equiv), DCM (15 mL) and DIPEA (2.06 g, 15.9 mmol, 1.99equiv). 4-Nitrophenyl chloroformate (1.78 g, 8.83 mmol, 1.11 equiv) inDCM (5 mL) was added dropwise at 0° C. The mixture was stirred for 2 hat room temperature. Then t-butyl1,8-diazaspiro[4.5]decane-1-carboxylate (1.92 g, 7.99 mmol, 1.00 equiv)was added. The resulting solution was stirred overnight at roomtemperature and quenched by water (20 mL), as described in Example 2,Step 6. The residue was chromatographed on a silica gel column toprovide 2.23 g (71% yield) of t-butyl8-(3-acetamido-1H-pyrazole-1-carbonyl)-1,8-diazaspiro[4.5]decane-1-carboxylateas an off-white solid. LCMS (ESI, m/z): 392 [M+H]⁺.

Step 2: Preparation ofN-(1-(1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazol-3-yl)acetamide

A flask was charged with of t-butyl8-(3-acetamido-1H-pyrazole-1-carbonyl)-1,8-diazaspiro[4.5]decane-1-carboxylate(2.23 g, 5.70 mmol, 1.00 equiv), DCM (20 mL) and TFA (10 mL), asdescribed in Example 1, Step 3. The resulting solution was stirredovernight at room temperature and concentrated under reduced pressure toprovide 1.58 g (crude) ofN-(1-(1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazol-3-yl)acetamide asa light yellow oil. LCMS (ESI, m/z): 292 [M+H]⁺.

Step 3: Preparation of ethyl(E)-2-(2-(2,4-dichlorophenyl)hydrazineylidene)propanoate

A 250-mL round-bottom flask was charged with(2,4-dichlorophenyl)hydrazine (10.0 g, 56.8 mmol, 1.00 equiv), ethanol(50 mL), ethyl 2-oxopropanoate (6.59 g, 56.8 mmol, 1.00 equiv) andtriethylamine (5.74 g, 56.8 mmol, 1.50 equiv). The resulting solutionwas refluxed overnight and concentrated under reduced pressure. Theresidue was chromatographed on a silica gel column to provide 3.15 g(31% yield) of ethyl(E)-2-(2-(2,4-dichlorophenyl)hydrazineylidene)propanoate as a lightyellow solid. LCMS (ESI, m/z): 275 [M+H]⁺.

Step 4: Preparation of ethyl 5,7-dichloro-1H-indole-2-carboxylate

A flask was charged with ethyl(2E)-2-[2-(2,4-dichlorophenyl)hydrazin-1-ylidene]propanoate (3.00 g,10.9 mmol, 1.00 equiv), acetic acid (50 mL) and zinc chloride (27.2 g,200 mmol, 18.3 equiv). The resulting solution was refluxed forovernight, cooled to room temperature and poured into water (200 mL).The solid was collected by filtration, washed with water (3×10 mL), anddried to provide 2.30 g (82% yield) of ethyl5,7-dichloro-1H-indole-2-carboxylate as a brown solid. LCMS (ESI, m/z):258 [M+H]⁺.

Step 5: Preparation of (5,7-dichloro-1H-indo1-2-yl)methanol

A vial was charged with ethyl 5,7-dichloro-1H-indole-2-carboxylate (500mg, 1.94 mmol, 1.00 equiv), THF (10 mL) and lithium aluminum hydride(111 mg, 2.92 mmol, 1.51 equiv). The resulting solution was stirredovernight at room temperature under nitrogen. Then water (111 ml), 15%sodium hydroxide solution (111 mg) and water (333 mL) were added insequence at 0° C. The solids were filtered out and washed with THF (3×10mL). The filtrate was concentrated under reduced pressure to provide 339mg (81% yield) of (5,7-dichloro-1H-indol-2-yl)methanol as a brown oil.LCMS (ESI, m/z): 216 [M+H]⁺.

Step 6: Preparation of 5,7-dichloro-1H-indole-2-carbaldehyde

A vial was charged with (5,7-dichloro-1H-indol-2-yl)methanol (0.339 g,1.57 mmol, 1.00 equiv), DCE (10 mL) and manganese dioxide (1.37 g, 15.8mmol, 10.0 equiv). The resulting solution was stirred overnight at roomtemperature. The solids were filtered out and washed with DCE (3×10 mL).The filtrate was concentrated under reduced pressure. The residue waschromatographed on a silica gel column to provide 0.203 g (60% yield) of5,7-dichloro-1H-indole-2-carbaldehyde as a brown oil. LCMS (ESI, m/z):214 [M+H]⁺.

Step 7: Preparation ofN-(1-(1-((5,7-dichloro-1H-indol-2-yl)methyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazol-3-yl)acetamide

A vial was charged with 5,7-dichloro-1H-indole-2-carbaldehyde (102 mg,0.477 mmol, 1.00 equiv), DCE (10 mL) andN-(1-[1,8-diazaspiro[4.5]decan-8-ylmethyl]-1H-pyrazol-3-yl)acetamide(132 mg, 0.477 mmol, 1.00 equiv). The mixture was stirred for 2 h atroom temperature. Then sodium triacetoxyborohydride (253 mg, 1.19 mmol,2.51 equiv) was added. The resulting solution was stirred overnight atroom temperature and quenched by water (10 mL), as described in Example1, Step 6. The crude product was purified by preparative HPLC to provide59.7 mg (26% yield) ofN-(1-(1-((5,7-dichloro-1H-indol-2-yl)methyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazol-3-yl)acetamideas a light yellow oil. ¹H NMR (400 MHz, Chloroform-d) δ 8.72 (br, 1H),7.90-8.15 (m, 2H), 7.35-7.50 (m, 1H), 7.12-7.15 (m, 1H), 6.80-7.02 (m,1H), 6.30 (d, J=2.7 Hz, 1H), 4.48-4.72 (m, 2H), 3.79 (s, 2H), 3.02 (m,2H), 2.62-2.85 (m, 2H), 2.18 (s, 3H), 1.80-1.98 (m, 6H), 1.45-1.59 (m,2H). LCMS (ESI, m/z): 489 [M+H]⁺.

Example 142-((8-(3-acetamido-1H-pyrazole-1-carbonyl)-1,8-diazaspiro[4.5]decan-1-yl)methyl)-1H-indole-5-carboxamide

Step 1: Synthesis of t-butyl8-(3-acetamido-1H-pyrazole-1-carbonyl)-1,8-diazaspiro[4.5]decane-1-carboxylate

A flask was charged with N-(1H-pyrazol-4-yl)acetamide (1.00 g, 7.99mmol, 1.00 equiv), DCM (15 mL) and DIPEA (2.06 g, 15.9 mmol, 2.00equiv). 4-Nitrophenyl chloroformate (1.78 g, 8.83 mmol, 1.11 equiv) inDCM (5 mL) was added dropwise at 0° C. The mixture was stirred for 2 hat room temperature, then t-butyl1,8-diazaspiro[4.5]decane-1-carboxylate (1.92 g, 7.99 mmol, 1.00 equiv)was added. The resulting solution was stirred overnight at roomtemperature and quenched by water (20 mL). The mixture was extractedwith DCM (3×20 mL) and the organic layers were combined, washed withwater (3×20 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was chromatographed toprovide 2.23 g (71% yield) of t-butyl8-(3-acetamido-1H-pyrazole-1-carbonyl)-1,8-diazaspiro[4.5]decane-1-carboxylateas an off-white solid. LCMS (ESI, m/z): 392 [M+H]⁺.

Step 2: Synthesis ofN-(1-(1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazol-3-yl)acetamide

A round-bottom flask was charged with t-butyl8-(3-acetamido-1H-pyrazole-1-carbonyl)-1,8-diazaspiro[4.5]decane-1-carboxylate(2.23 g, 5.70 mmol, 1.00 equiv), DCM (10 mL) and TFA (3 mL), asdescribed in Example 1, Step 3. The resulting solution was stirredovernight at room temperature and concentrated under reduced pressure toprovide 1.58 g (crude) ofN-(1-(1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazol-3-yl)acetamide asa light yellow oil. LCMS (ESI, m/z): 292 [M+H]⁺.

Step 3: Preparation of methyl 4-amino-3-iodobenzoate

A flask was charged with methyl 4-aminobenzoate (9.00 g, 59.5 mmol, 1.00equiv), THF (100 mL) and 1-iodo-5-pyrrolidinedione (16.2 g, 72.0 mmol,1.20 equiv). The resulting solution was stirred overnight at roomtemperature and concentrated under reduced pressure. The residue wasdiluted with water (50 mL) and extracted with DCM (3×50 mL), the organiclayers were combined, washed with water (3×50 mL), dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was chromatographed on a silica gel column to provide 7.60 g(46% yield) of methyl 4-amino-3-iodobenzoate as a yellow solid. LCMS(ESI, m/z): 278 [M+H]⁺.

Step 4: Preparation of methyl3-iodo-4-(2,2,2-trifluoroacetamido)benzoate

A round-bottom flask was charged with methyl 4-amino-3-iodobenzoate(7.50 g, 27.1 mmol, 1.00 equiv), DCM (50 mL), triethylamine (7.20 g,71.3 mmol, 2.63 equiv) and trifluoroacetic anhydride (8.90 g, 42.4 mmol,1.57 equiv). The resulting solution was stirred overnight at roomtemperature and washed with water (3×50 mL). The organic layer was driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure, as described in Example 1, Step 1. The residue waschromatographed on a silica gel column to provide 8.00 g (79% yield) ofmethyl 3-iodo-4-(2,2,2-trifluoroacetamido)benzoate as a yellow solid.

Step 5: Preparation of methyl 2-(hydroxymethyl)-1H-indole-5-carboxylate

A three-necked round-bottom flask was charged with methyl3-iodo-4-(2,2,2-trifluoroacetamido)benzoate (3.73 g, 10.0 mmol, 1.00equiv), N,N-dimethylformamide (50 mL), prop-2-yn-1-ol (0.840 g, 15.0mmol, 1.50 equiv), triethylamine (5.05 g, 50.0 mmol, 5.00 equiv),cuprous iodide (0.190 g, 1.00 mmol, 0.10 equiv) andbis(triphenylphosphine)palladium(II) chloride (0.350 g, 0.500 mmol, 0.05equiv) under nitrogen. The resulting solution was stirred overnight at60° C. and diluted with water (500 mL). The mixture was extracted withEtOAc (3×500 mL) and the organic layers were combined, washed with water(3×100 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was chromatographed ona silica gel column to provide 1.80 g (85% yield) of methyl2-(hydroxymethyl)-1H-indole-5-carboxylate as a brown oil. LCMS (ESI,m/z): 206 [M+H]⁺.

Step 6: Preparation of 2-(hydroxymethyl)-1H-indole-5-carboxylic acid

A vial was charged with methyl 2-(hydroxymethyl)-1H-indole-5-carboxylate(800 mg, 3.90 mmol, 1.00 equiv), methanol (5 mL), water (5 mL) andsodium hydroxide (234 mg, 5.85 mmol, 1.50 equiv). The resulting solutionwas stirred overnight at 60° C. and concentrated under reduced pressure.The residue was diluted with water (25 mL) and the pH value was adjustedto 4˜5 with 1 N hydrochloric acid solution, as described in Example 4,Step 3. The solid was collected by filtration, washed with water (3×10mL) and dried to provide 620 mg (83% yield) of2-(hydroxymethyl)-1H-indole-5-carboxylic acid as a light brown solid.LCMS (ESI, m/z): 192 [M+H]⁺.

Step 7: Preparation of 2-formyl-1H-indole-5-carboxylic acid

A vial was charged with 2-(hydroxymethyl)-1H-indole-5-carboxylic acid(0.300 g, 1.57 mmol, 1.00 equiv), ether (10 mL) and manganese dioxide(1.37 g, 15.7 mmol, 10.0 equiv). The resulting solution was stirredovernight at room temperature. The solid was filtered out and washedwith acetonitrile (3×10 mL), as described in Example 13, Step 6 toprovide 0.189 g (64% yield) of 2-formyl-1H-indole-5-carboxylic acid as ayellow oil. LCMS (ESI, m/z): 190 [M+H]⁺.

Step 8: Preparation of2-((8-(3-acetamido-1H-pyrazole-1-carbonyl)-1,8-diazaspiro[4.5]decan-1-yl)methyl)-1H-indole-5-carboxylicacid

A vial was charged with 2-formyl-1H-indole-5-carboxylic acid (137 mg,0.725 mmol, 1.00 equiv), DCE (10 mL) andN-(1-(1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazol-3-yl)acetamide(211 mg, 0.725 mmol, 1.00 equiv) and sodium triacetoxyborohydride (385mg, 1.82 mmol, 2.50 equiv). The resulting solution was stirred overnightat room temperature and quenched by water (10 mL), as described inExample 1, Step 6. The residue was chromatographed on a silica gelcolumn to provide 75.0 mg (22% yield) of2-((8-(3-acetamido-1H-pyrazole-1-carbonyl)-1,8-diazaspiro[4.5]decan-1-yl)methyl)-1H-indole-5-carboxylicacid as a yellow oil. LCMS (ESI, m/z): 465 [M+H]⁺.

Step 9: Preparation of2-((8-(3-acetamido-1H-pyrazole-1-carbonyl)-1,8-diazaspiro[4.5]decan-1-yl)methyl)-1H-indole-5-carboxamide

A vial was charged with2-((8-(3-acetamido-1H-pyrazole-1-carbonyl)-1,8-diazaspiro[4.5]decan-1-yl)methyl)-1H-indole-5-carboxylicacid (75.0 mg, 0.161 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL),DIPEA (41.5 mg, 0.322 mmol, 2.00 equiv),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (34.0 mg,0.177 mmol, 1.10 equiv) and 1-hydroxybenzotrizole (23.9 mg, 0.177 mmol,1.10 equiv). The mixture was stirred for 2 hours at room temperature.Then ammonium chloride (12.8 mg, 0.242 mmol, 1.50 equiv) was added. Theresulting solution was stirred overnight at room temperature andquenched by water (50 mL). The mixture was extracted with EtOAc (3×50mL) and the organic layers were combined, washed with water (3×50 mL),dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The crude product was purified by preparative HPLC toprovide 14.9 mg (20% yield) of2-((8-(3-acetamido-1H-pyrazole-1-carbonyl)-1,8-diazaspiro[4.5]decan-1-yl)methyl)-1H-indole-5-carboxamideas a light yellow solid. ¹H NMR (300 MHz, Methanol-d₄) δ 7.99-8.17 (m,2H), 7.58-7.80 (m, 1H), 7.30-7.48 (m, 1H), 6.72-6.89 (m, 1H), 6.31 (s,1H), 4.50-4.70 (m, 2H), 3.85 (s, 2H), 3.08-3.26 (m, 2H), 2.78-2.90 (m,2H), 2.14 (s, 3H), 1.78-2.05 (m, 6H), 1.53-1.65 (m, 2H). LCMS (ESI,m/z): 464 [M+H]⁺.

Example 15N-(1-(4-(2-(thiazol-2-yl)-4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

Step 1: Preparation of t-butyl4-(2-bromo-4-(trifluoromethyl)phenoxy)piperidine-1-carboxylate

A flask was charged with t-butyl 4-hydroxypiperidine-1-carboxylate (2.0g, 9.94 mmol, 1.00 equiv) and THF (40 mL). Then sodium hydride (60% inoil, 0.800 g, 20.0 mmol, 2.00 equiv) was added at 0° C. The resultingsolution was stirred for 1 hour at room temperature and2-bromo-1-fluoro-4-(trifluoromethyl)benzene (3.20 g, 13.2 mmol, 1.30equiv) was added. The resulting solution was stirred overnight at roomtemperature and quenched by water (20 mL), as described in Example 4,Step 1. The residue was chromatographed on a silica gel column toprovide 3.40 g (81% yield) t-butyl4-(2-bromo-4-(trifluoromethyl)phenoxy)piperidine-1-carboxylate as awhite solid. LCMS (ESI, m/z): 424 [M+H]⁺.

Step 2: Preparation of t-butyl4-(2-(thiazol-2-yl)-4-(trifluoromethyl)phenoxy)piperidine-1-carboxylate

A flask was charged with t-butyl4-[2-bromo-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (424 mg,1.00 mmol, 1.00 equiv), tetrakis(triphenylphosphane) palladium (104 mg,0.100 mmol, 0.10 equiv), 2-(tributylstannyl)-1,3-thiazole (450 mg, 1.20mmol, 1.20 equiv) and toluene (20 mL). The resulting solution wasstirred overnight at 80° C. under nitrogen and quenched by water (20mL). The mixture was extracted with DCM (3×30 mL) and the organic layerswere combined, washed with water (3×10 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas chromatographed on a silica gel column to provide 259 mg (60% yield)of t-butyl4-(2-(thiazol-2-yl)-4-(trifluoromethyl)phenoxy)piperidine-1-carboxylateas a yellow solid. LCMS (ESI, m/z): 429 [M+H]⁺.

Step 3: Preparation of2-(2-(piperidin-4-yloxy)-5-(trifluoromethyl)phenyl)thiazole

A flask was charged with t-butyl4-[2-(1,3-thiazol-2-yl)-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate(259 mg, 0.60 mmol, 1.00 equiv), 1,4-dioxane (20 mL) and hydrochloricacid (4 mL), as described in Example 11, Step 5. The resulting solutionwas stirred for 2 h at room temperature and concentrated under reducedpressure to provide 195 mg (crude) of2-(2-(piperidin-4-yloxy)-5-(trifluoromethyl)phenyl)thiazole as a whitesolid. LCMS (ESI, m/z): 329 [M+H]⁺.

Step 4: Preparation of4-(2-(thiazol-2-yl)-4-(trifluoromethyl)phenoxy)piperidine-1-carbonylchloride

A flask was charged with2-(2-(piperidin-4-yloxy)-5-(trifluoromethyl)phenyl)thiazole (195 mg,0.590 mmol, 1.00 equiv), triphosgene (89.0 mg, 0.300 mmol, 0.50 equiv)and DCM (20 mL). Then DIPEA (307 mg, 2.38 mmol, 4.00 equiv) was added at0° C. The resulting solution was stirred for 2 h at room temperature andquenched by water (10 mL), as described in Example 2, Step 5 to provide230 mg (crude) of4-[2-(1,3-thiazol-2-yl)-4-(trifluoromethyl)phenoxy]piperidine-1-carbonylchloride as a white solid.

Step 5: Preparation ofN-(1-(4-(2-(thiazol-2-yl)-4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

A flask was charged with4-[2-(1,3-thiazol-2-yl)-4-(trifluoromethyl)phenoxy]piperidine-1-carbonylchloride (232 mg, 0.590 mmol, 1.00 equiv), 4-dimethylaminopyridine (14.5mg, 0.118 mmol, 0.200 equiv), DIPEA (153 mg, 1.18 mmol, 2.00 equiv),N-(1H-pyrazol-3-yl)methanesulfonamide (118 mg, 0.730 mmol, 1.00 equiv)and THF (20 mL). The resulting solution was stirred overnight at 60° C.and quenched by water (10 mL), as described in Example 2, Step 6. Thecrude product was purified by preparative HPLC to provide 64.0 mg (21%yield) ofN-(1-(4-(2-(thiazol-2-yl)-4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamideas a white solid. ¹H NMR (300 MHz, Chloroform-d) δ 8.75-8.80 (m, 1H),8.05-8.15 (m, 1H), 7.91-8.02 (m, 1H), 7.55-7.68 (m, 1H), 7.40-7.50 (m,1H), 7.01-7.20 (m, 1H), 6.30 (s, 1H), 5.00 (s, 1H), 3.81-4.25 (m, 4H),3.11 (s, 3H), 2.05-2.31 (m, 4H). LCMS (ESI, m/z): 516 [M+H]⁺.

Example 16N-(1-(5-(3-chloro-5-(2-hydroxypropan-2-yl)benzyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazol-3-yl)acetamide

Step 1: Synthesis of 2-(3-bromo-5-chlorophenyl)propan-2-ol

A flask was charged with methyl 3-bromo-5-chlorobenzoate (1.50 g, 6.05mmol, 1.00 equiv), THF (10 mL) under nitrogen. The mixture was cooled to−78° C. Methylmagnesium bromide (6.05 mL, 18.2 mmol, 3.00 equiv, 3 M inethyl ether) was added dropwise at −78° C. The resulting solution wasstirred overnight at room temperature and quenched with saturated NH₄Clsolution (30 mL). The resulting solution was extracted with DCM (2×50mL) and the organic layers were combined, washed with brine (2×30 mL),dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was chromatographed on a silica gel columnto provide 1.40 g (93% yield) of 2-(3-bromo-5-chlorophenyl)propan-2-olas an off-white solid.

Step 2: Preparation of 3-chloro-5-(2-hydroxypropan-2-yl)benzaldehyde

A flask was charged with 2-(3-bromo-5-chlorophenyl)propan-2-ol (1.40 g,5.65 mmol, 1.00 equiv) and THF (10 mL) under nitrogen. The mixture wascooled to −78° C. n-Butyllithium (4.52 mL, 11.3 mmol, 2.00 equiv, 2.5 Min hexane) was added dropwise at −78° C. The mixture was stirred for 30min at −78° C. and N,N-dimethylformamide (1.24 g, 17.0 mmol, 3.00 equiv)was added. The resulting solution was stirred for 1 h at −78° C. andquenched with saturated NH₄Cl solution (30 mL), as described in Example7, Step 3. The residue was chromatographed on a silica gel column toprovide 360 mg (32% yield) of3-chloro-5-(2-hydroxypropan-2-yl)benzaldehyde as a off-white solid. ¹HNMR (300 MHz, Chloroform-d) δ 10.01 (s, 1H), 7.89 (s, 1H), 7.84-7.72 (m,2H), 1.64 (s, 6H).

Step 3: Preparation of t-butyl5-(3-acetamido-1H-pyrazole-1-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

A flask was charged with triphosgene (0.980 g, 3.30 mmol, 0.70 equiv)and DCM (25 mL). N-(1H-pyrazol-3-yl)acetamide (1.06 g, 8.50 mmol, 1.80equiv) was added at 0° C. DIPEA (2.44 g, 18.9 mmol, 4.00 equiv) wasadded at 0° C. and the mixture was stirred for 2 h at room temperature.t-Butyl octahydropyrrolo[3,4-c]pyrrole-2-carboxylate (1.00 g, 4.72 mmol,1.00 equiv) was added. The resulting solution was stirred overnight atroom temperature and then quenched with water (10 mL), as described inExample 2, Step 5. The residue was chromatographed on a silica gelcolumn to provide 1.10 g (38% yield) of t-butyl5-(3-acetamido-1H-pyrazole-1-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylateas a yellow oil. LCMS (ESI, m/z): 364 [M+H]⁺.

Step 4: Preparation ofN-(1-(octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazol-3-yl)acetamide

A flask was charged with t-butyl5-(3-acetamido-1H-pyrazole-1-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(400 mg, 1.10 mmol, 1.00 equiv), DCM (10 mL), and TFA (2 mL). Theresulting solution was stirred for 2 h at room temperature andconcentrated under reduced pressure as described in Example 1, Step 3 toprovide 420 mg (crude) ofN-(1-(octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazol-3-yl)acetamideas a yellow oil. LCMS (ESI, m/z): 264 [M+H]⁺.

Step 5: Preparation ofN-(1-(5-(3-chloro-5-(2-hydroxypropan-2-yl)benzyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazol-3-yl)acetamide

A flask was charged withN-(1-(octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazol-3-yl)acetamide(192 mg, 0.730 mmol, 1.20 equiv),3-chloro-5-(2-hydroxypropan-2-yl)benzaldehyde (120 mg, 0.610 mmol, 1.00equiv), and DCE (15 mL). The mixture was stirred for 1 h at roomtemperature. Sodium triacetoxyborohydride (517 mg, 2.44 mmol, 4.00equiv) was added. The resulting solution was stirred overnight at roomtemperature and then quenched with water (10 mL), as described inExample 1, Step 6. The crude product (120 mg) was purified bypreparative HPLC to provide 32.3 mg (12% yield) ofN-(1-(5-(3-chloro-5-(2-hydroxypropan-2-yl)benzyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazol-3-yl)acetamideas a white solid. ¹H NMR (300 MHz, Chloroform-d) δ 8.11-8.12 (m, 2H),7.44 (s, 1H), 7.31 (s, 1H), 7.16 (s, 1H), 6.87 (d, J=2.7 Hz, 1H), 3.91(br, 4H), 3.59 (s, 2H), 2.88 (br, 2H), 2.61-2.64 (m, 4H), 2.19 (s, 4H),1.57 (s, 6H). LCMS (ESI, m/z): 446 [M+H]⁺.

Example 17

N-(1-(4-(3-chloro-5-(4-chlorophenoxy)benzyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)acetamide

Step 1: Preparation of bis(4-chlorophenyl)iodonium tetrafluoroborate

A flask was charged with meta-chloroperoxybenzoic acid (1.60 g, 9.27mmol, 1.10 equiv), DCM (10 mL), boron trifluoride diethyl ether complex(3.58 g, 25.2 mmol, 3.00 equiv) and 1-chloro-4-iodobenzene (2.00 g, 8.39mmol, 1.00 equiv). The resulting solution was stirred for 0.5 h at roomtemperature. Then (4-chlorophenyl)boronic acid (1.44 g, 9.22 mmol, 1.10equiv) was added at 0° C. The resulting solution was stirred for 20 minat room temperature and concentrated under reduced pressure. The crudeproduct was triturated to provide 3.00 g (78% yield) ofbis(4-chlorophenyl)iodonium tetrafluoroborate as a white solid. LCMS(ESI, m/z): 349 [M−BF₄ ⁻]⁺.

Step 2: Preparation of 4-nitrophenyl3-acetamido-1H-pyrazole-1-carboxylate

A flask was charged with N-(1H-pyrazol-3-yl)acetamide (120 mg, 0.960mmol, 1.00 equiv), DCM (10 mL), 4-nitrophenyl chloroformate (203 mg,1.01 mmol, 1.05 equiv), and triethylamine (291 mg, 2.88 mmol, 3.00equiv), as described in Example 1, Step 1. The resulting solution wasstirred for 3 h at room temperature and concentrated under reducedpressure to provide 280 mg (crude) of 4-nitrophenyl3-acetamido-1H-pyrazole-1-carboxylate as a yellow oil. LCMS (ESI, m/z):291 [M+H]⁺.

Step 3: Preparation of t-butyl4-(3-chloro-5-hydroxybenzyl)piperazine-1-carboxylate

A flask was charged with 3-chloro-5-hydroxybenzaldehyde (300 mg, 1.92mmol, 1.00 equiv), DCE (10 mL), t-butyl piperazine-1-carboxylate (536mg, 2.88 mmol, 1.50 equiv), and triethylamine (582 mg, 5.76 mmol, 3.00equiv). The resulting solution was stirred for 1 h at room temperature.Sodium triacetoxyborohydride (1.21 g, 5.76 mmol, 3.00 equiv) was added.The resulting solution was stirred overnight at room temperature andquenched with water (20 mL), as described in Example 1, Step 6. Theresidue was chromatographed on a silica gel column to provide 460 mg(73% yield) of t-butyl4-(3-chloro-5-hydroxybenzyl)piperazine-1-carboxylate as a white solid.LCMS (ESI, m/z): 327 [M+H]⁺.

Step 4: Preparation of t-butyl4-(3-chloro-5-(4-chlorophenoxy)benzyl)piperazine-1-carboxylate

A flask was charged with t-butyl4-(3-chloro-5-hydroxybenzyl)piperazine-1-carboxylate (160 mg, 0.491mmol, 1.00 equiv), THF (10 mL), sodium hydroxide (21.6 mg, 0.540 mmol,1.10 equiv). The resulting solution was stirred for 15 min at 0° C. Thenbis(4-chlorophenyl)iodanium tetrafluoroborate (235 mg, 0.540 mmol, 1.10equiv) was added. The resulting solution was stirred overnight at 40° C.and quenched with water (10 mL), as described in Example 4, Step 3. Theresidue was chromatographed on a silica gel column to provide 60.0 mg(28% yield) of t-butyl4-(3-chloro-5-(4-chlorophenoxy)benzyl)piperazine-1-carboxylate as acolorless oil. LCMS (ESI, m/z): 437 [M+H]⁺.

Step 5: Preparation of 1-(3-chloro-5-(4-chlorophenoxy)benzyl)piperazine

A flask was charged with t-butyl4-(3-chloro-5-(4-chlorophenoxy)benzyl)piperazine-1-carboxylate (60.0 mg,0.138 mmol, 1.00 equiv), DCM (5 mL), and TFA (1 mL), as described inExample 1, Step 3. The resulting solution was stirred for 1 h at roomtemperature and concentrated under reduced pressure to provide 60.0 mg(crude) of 1-(3-chloro-5-(4-chlorophenoxy)benzyl)piperazine as a yellowoil. LCMS (ESI, m/z): 337 [M+H]⁺.

Part 6: Preparation ofN-(1-(4-(3-chloro-5-(4-chlorophenoxy)benzyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)acetamide

A flask was charged with1-(3-chloro-5-(4-chlorophenoxy)benzyl)piperazine (60.0 mg, 0.179 mmol,1.00 equiv), DCM (10 mL), 4-nitrophenyl3-acetamido-1H-pyrazole-1-carboxylate (104 mg, 0.360 mmol, 2.00 equiv),and triethylamine (54.2 mg, 0.537 mmol, 3.00 equiv). The resultingsolution was stirred overnight at room temperature and quenched withwater (10 mL, as described in Example 1, Step 1. The crude product (200mg) was purified by preparative HPLC to provide 7.10 mg (8% yield) ofN-(1-(4-(3-chloro-5-(4-chlorophenoxy)benzyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)acetamideas a white solid. ¹H NMR (300 MHz, Chloroform-d) δ 8.02 (d, J=2.7 Hz,1H), 7.72 (br, 1H), 7.30-7.37 (m, 2H), 7.11 (s, 1H), 6.94-7.00 (m, 2H),6.88-6.91 (m, 3H), 3.88 (br, 4H), 3.53 (br, 2H), 2.56 (br, 4H), 2.19 (s,3H). LCMS (ESI, m/z): 488 [M+H]⁺.

Example 18N-(1-(5-(3-(2-chlorophenoxy)benzyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazol-3-yl)acetamide

Step 1: Preparation of t-butyl5-(chlorocarbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

A flask was charged with triphosgene (1.78 g, 5.99 mmol, 0.60 equiv),and DCM (50 mL). t-Butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (2.12 g, 9.99 mmol,1.00 equiv) and DIPEA (3.87 g, 29.9 mmol, 3.00 equiv) were added at 0°C. The resulting solution was stirred for 2 h at room temperature andquenched with water (30 mL), as described in Example 2, Step 5 toprovide 2.75 g (crude) of t-butyl5-(chlorocarbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate as ayellow oil. LCMS (ESI, m/z): 275 [M+H]⁺.

Step 2: Preparation of t-butyl5-(3-acetamido-1H-pyrazole-1-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

A flask was charged with t-butyl5-(chlorocarbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (5.50g, 20.0 mmol, 1.00 equiv), N-(1H-pyrazol-3-yl)acetamide (2.75 g, 22.0mmol, 1.10 equiv), 4-dimethylaminopyridine (246 mg, 2.01 mmol, 0.10equiv), THF (100 mL), and DIPEA (7.74 g, 59.9 mmol, 3.00 equiv). Theresulting solution was stirred overnight at 60° C. and quenched withwater (100 mL), as described in Example 2, Step 6. The residue waschromatographed on a silica gel column to provide 3.738 g (51% yield) oft-butyl5-(3-acetamido-1H-pyrazole-1-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylateas a light yellow solid. LCMS (ESI, m/z): 364 [M+H]⁺.

Step 3: Preparation ofN-(1-(octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazol-3-yl)acetamide

A flask was charged with t-butyl5-(3-acetamido-1H-pyrazole-1-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(1.70 g, 4.68 mmol, 1.00 equiv), DCM (25 mL), and TFA (5 mL), asdescribed in Example 1, Step 3 to provide 1.23 g (crude)N-(1-(octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazol-3-yl)acetamideas a yellow oil. LCMS (ESI, m/z): 264 [M+H]⁺.

Step 4: Preparation of 3-(2-chlorophenoxy)benzaldehyde

A flask was charged with 2-chlorophenol (5.12 g, 39.8 mmol, 2.00 equiv),3-bromobenzaldehyde (3.70 g, 20.0 mmol, 1.00 equiv), cesium carbonate(19.6 g, 60.1 mmol, 3.00 equiv), L-proline (123 mg, 1.06 mmol, 0.05equiv), copper(I)iodide (382 mg, 2.01 mmol, 0.10 equiv), andN,N-dimethylformamide (150 mL) under nitrogen. The resulting solutionwas stirred overnight at 120° C. and quenched with water (50 mL). Themixture was extracted with EtOAc (3×50 mL) and the organic layers werecombined, washed with brine (3×50 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas chromatographed on a silica gel column to provide 0.610 g (13%yield) of 3-(2-chlorophenoxy)benzaldehyde as a yellow oil. LCMS (ESI,m/z): 233 [M+H]⁺.

Step 5: Preparation ofN-(1-(5-(3-(2-chlorophenoxy)benzyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazol-3-yl)acetamide

A flask was charged with 3-(2-chlorophenoxy)benzaldehyde (116 mg, 0.501mmol, 1.00 equiv),N-(1-(octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazol-3-yl)acetamide(131 mg, 0.501 mmol, 1.00 equiv), DCE (5 mL), and triethylamine (151 mg,1.49 mmol, 3.00 equiv). The resulting solution was stirred for 2 h atroom temperature. Sodium triacetoxyborohydride (318 mg, 1.50 mmol, 3.00equiv) was added. The resulting solution was stirred overnight at roomtemperature and quenched with water (20 mL), as described in Example 1,Step 6. The crude product (269 mg) was purified by preparative HPLC toprovide 107.7 mg (45% yield) ofN-(1-(5-(3-(2-chlorophenoxy)benzyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazol-3-yl)acetamideas a white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.13 (d, J=2.8 Hz,1H), 7.84 (br, 1H), 7.43-7.45 (m, 1H), 7.24-7.28 (m, 1H), 7.18-7.23 (m,1H), 7.03-7.08 (m, 2H), 6.93-7.01(m, 2H), 6.81-6.90 (m, 2H), 4.04 (br,2H),3.73 (br, 2H), 3.58 (s, 2H), 2.86 (br, 2H), 2.50-2.70 (m, 4H), 2.17(s, 3H). LCMS (ESI, m/z): 480 [M+H]⁺.

Example 19:N-(1-(4-(methyl(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)phenyl)amino)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

Step 1: Synthesis of 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate

A flask was charged with N-(1H-pyrazol-3-yl)methanesulfonamide (4.50 g,27.9 mmol, 1.00 equiv), 4-nitrophenyl chloroformate (5.90 g, 29.3 mmol,1.05 equiv), DCM (50 mL), and triethylamine (8.50 g, 84.0 mmol, 3.00equiv). The resulting solution was stirred for 2 h at room temperatureand concentrated under reduced pressure, as described in Example 1, Step1 to provide 10.0 g (crude) of 4-nitrophenyl3-methanesulfonamido-1H-pyrazole-1-carboxylate as a yellow solid. LCMS(ESI, m/z): 327 [M+H]⁺.

Step 2: Preparation of t-butyl4-((2-bromo-4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate

A flask was charged with t-butyl 4-aminopiperidine-1-carboxylate (416mg, 2.06 mmol, 2.00 equiv), 2-bromo-1-fluoro-4-(trifluoromethyl)benzene(250 mg, 1.03 mmol, 1.00 equiv), DIPEA (403 mg, 3.09 mmol, 3.00 equiv),and dimethyl sulfoxide (10 mL), as described in Example 1, Step 5. Theresidue was chromatographed on a silica gel column to provide 420 mg(96% yield) of t-butyl4-((2-bromo-4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate asa yellow oil. LCMS (ESI, m/z): 423 [M+H]⁺.

Step 3: Preparation of t-butyl4-((2-bromo-4-(trifluoromethyl)phenyl)(methyl)amino)piperidine-1-carboxylate

A flask was charged with t-butyl4-((2-bromo-4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate(350 mg, 0.830 mmol, 1.00 equiv), N,N-dimethylformamide (10 mL), andsodium hydride (49.8 mg, 1.25 mmol, 1.50 equiv, 60% in mineral oil). Theresulting solution was stirred for 1 h at 0° C. Methyl iodide (176 mg,1.24 mmol, 1.50 equiv) was added. The resulting solution was stirredovernight at room temperature and quenched with water (10 mL). Theresulting solution was extracted with EtOAc (3×10 mL) and the organiclayers were combined, washed with brine (2×10 mL), dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was chromatographed on a silica gel column to provide 290 mg(98% yield) of t-butyl4-((2-bromo-4-(trifluoromethyl)phenyl)(methyl)amino)piperidine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 437 [M+H]⁺.

Step 4: Preparation of t-butyl4-(methyl(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate

A flask was charged with t-butyl4-((2-bromo-4-(trifluoromethyl)phenyl)(methyl)amino)piperidine-1-carboxylate(380 mg, 0.870 mmol, 1.00 equiv), pyrrolidine (124 mg, 1.74 mmol, 2.00equiv), tris(dibenzylideneacetone)dipalladium (39.8 mg, 0.0435 mmol,0.05 equiv), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (81.3 mg, 0.130mmol, 0.15 equiv), cesium carbonate (851 mg, 2.61 mmol, 3.00 equiv), andtoluene (10 mL) under nitrogen. The resulting solution was stirredovernight at 90° C. and quenched with water (10 mL), as described inExample 9, Step 1. The residue was chromatographed on a silica gelcolumn to provide 130 mg (35% yield) of t-butyl4-(methyl(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 428 [M+H]⁺.

Step 5: Preparation ofN-methyl-N-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)phenyl)piperidin-4-amine

A flask was charged with t-butyl4-(methyl(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate(130 mg, 0.304 mmol, 1.00 equiv), 1,4-dioxane (5 mL), and concentratedhydrochloric acid (1 mL), as described in Example 11, Step 5 to provide150 mg (crude) ofN-methyl-N-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)phenyl)piperidin-4-amineas a yellow oil. LCMS (ESI, m/z): 328 [M+H]⁺.

Step 6: Preparation ofN-(1-(4-(methyl(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)phenyl)amino)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

A flask was charged withN-methyl-N-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)phenyl)piperidin-4-amine(101 mg, 0.310 mmol, 1.00 equiv), 4-nitrophenyl3-methanesulfonamido-1H-pyrazole-1-carboxylate (202 mg, 0.620 mmol, 2.00equiv), DCM (10 mL), triethylamine (93.9 mg, 0.930 mmol, 3.00 equiv).The resulting solution was stirred for 3 h at room temperature andquenched with water (10 mL), as described in Example 1, Step 1. Thecrude product (200 mg) was purified by preparative HPLC to provide 65.1mg (41% yield) ofN-(1-(4-(methyl(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)phenyl)amino)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamideas a white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.02 (d, J=2.7 Hz,1H), 7.00-7.12 (m, 4H), 6.32 (d, J=2.7 Hz, 1H), 4.49-4.52 (m, 2H),3.44-3.52 (m, 1H), 3.26-3.29 (m, 4H), 3.13 (s, 3H), 2.98-3.03 (m, 2H),2.67 (s, 3H), 1.90-1.94 (m, 4H), 1.66-1.79 (m, 4H). LCMS (ESI, m/z): 515[M+H]⁺.

Example 20N-(1-(1-(4-chloro-3-cyclopropylbenzoyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazol-3-yl)acetamide

Step 1: Synthesis of t-butyl1-(3-bromo-4-chlorobenzoyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

A flask was charged with 3-bromo-4-chlorobenzoic acid (400 mg, 1.71mmol, 1.00 equiv), DCM (10 mL),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (493 mg,2.57 mmol, 1.50 equiv), and 1-hydroxybenzotrizole (347 mg, 2.57 mmol,1.50 equiv). The mixture was stirred for 30 min at room temperature.t-Butyl 1,8-diazaspiro[4.5]decane-8-carboxylate (616 mg, 2.57 mmol, 1.50equiv) was added. The resulting solution was stirred overnight at roomtemperature and quenched with water (30 mL), as described in Example 14,Step 8. The residue was chromatographed on a silica gel column toprovide 650 mg (84% yield) of t-butyl1-(3-bromo-4-chlorobenzoyl)-1,8-diazaspiro[4.5]decane-8-carboxylate as ayellow oil. LCMS (ESI, m/z): 457 [M+H]⁺.

Step 2: Prepartion of t-butyl1-(4-chloro-3-cyclopropylbenzoyl)-1,8-diazaspiro[4.5]decane-8-carboxylate

A 50-mL round-bottom flask was charged with t-butyl1-(3-bromo-4-chlorobenzoyl)-1,8-diazaspiro[4.5]decane-8-carboxylate (400mg, 0.877 mmol, 1.00 equiv), 1,4-dioxane (10 mL), water (2 mL),cyclopropylboronic acid (112 mg, 1.32 mmol, 1.50 equiv),tetrakis(triphenylphosphine)palladium (48.0 mg, 0.0400 mmol, 0.05equiv), and potassium carbonate (360 mg, 2.60 mmol, 3.00 equiv) undernitrogen. The resulting solution was stirred overnight at 80° C. andquenched with water (30 mL). The resulting solution was extracted withDCM (2×50 mL) and the organic layers were combined, washed with brine(2×30 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was chromatographed ona silica gel column to provide 280 mg (76% yield) of t-butyl1-(4-chloro-3-cyclopropylbenzoyl)-1,8-diazaspiro[4.5]decane-8-carboxylateas a light yellow oil. LCMS (ESI, m/z): 419 [M+H]⁺.

Step 3: Preparation of(4-chloro-3-cyclopropylphenyl)(1,8-diazaspiro[4.5]decan-1-yl)methanone

A flask was charged with t-butyl1-(4-chloro-3-cyclopropylbenzoyl)-1,8-diazaspiro[4.5]decane-8-carboxylate(200 mg, 0.480 mmol, 1.00 equiv), DCM (10 mL), and TFA (2 mL), asdescribed in Example 1, Step 3 to provide 210 mg (crude) of(4-chloro-3-cyclopropylphenyl)(1,8-diazaspiro[4.5]decan-1-yl)methanoneas a light yellow oil. LCMS (ESI, m/z): 319 [M+H]⁺.

Step 4: Preparation of1-(4-chloro-3-cyclopropylbenzoyl)-1,8-diazaspiro[4.5]decane-8-carbonylchloride

A flask was charged with triphosgene (70.0 mg, 0.240 mmol, 0.50 equiv),DCM (10 mL), and(4-chloro-3-cyclopropylphenyl)(1,8-diazaspiro[4.5]decan-1-yl)methanone(152 mg, 0.480 mmol, 1.00 equiv). DIPEA (185 mg, 1.44 mmol, 3.00 equiv)was added at 0° C. The resulting solution was stirred for 3 h at roomtemperature and quenched with water (30 mL), as described in Example 2,Step 5 to provide 180 mg (crude) of1-[(4-chloro-3-cyclopropylphenyl)carbonyl]-1,8-diazaspiro[4.5]decane-8-carbonylchloride as a yellow oil. LCMS (ESI, m/z): 381 [M+H]⁺.

Step 5: Preparation ofN-(1-(1-(4-chloro-3-cyclopropylbenzoyl)-1,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazol-3-yl)acetamide

A 50-mL round-bottom flask was charged1-[(4-chloro-3-cyclopropylphenyl)carbonyl]-1,8-diazaspiro[4.5]decane-8-carbonylchloride (175 mg, 0.460 mmol, 1.00 equiv), THF (10 mL),N-(1H-pyrazol-3-yl)acetamide (69.0 mg, 0.552 mmol, 1.20 equiv), DIPEA(184 mg, 1.43 mmol, 3.00 equiv), and 4-dimethylaminopyridine (12.0 mg,0.092 mmol, 0.20 equiv). The resulting solution was stirred overnight at60° C. and quenched with water (30 mL), as described in Example 2, Step6. The crude product (300 mg) was purified by preparative HPLC toprovide 27.7 mg (13% yield) ofN-[1-([1-[(4-chloro-3-cyclopropylphenyl)carbonyl]-1,8-diazaspiro[4.5]decan-8-yl]carbonyl)-1H-pyrazol-3-yl]acetamideas a white solid. ¹H NMR (300 MHz, Chloroform-d) δ 8.13 (br, 1H), 7.99(d, J=2.7 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.12-7.15 (m, 1H), 6.99 (s,1H), 6.72 (d, J=2.7 Hz, 1H), 4.52-4.56 (m, 2H), 3.40 (t, J=6.8 Hz, 2H),3.20-3.28 (m, 2H), 3.02-3.10 (m, 2H), 2.14-2.18 (m, 4H), 2.08 (t, J=6.8Hz, 2H), 1.78-1.87 (m, 2H), 1.51-1.87 (m, 2H), 1.01-1.06 (m, 2H),0.67-0.72 (m, 2H). LCMS (ESI, m/z): 470 [M+H]⁺.

Example 21N-(1-(4-(4-chloro-3-cyclopentylphenoxy)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

Step 1: Preparation of 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate

A vial was charged with N-(1H-pyrazol-3-yl)methanesulfonamide (172 mg,1.07 mmol, 1.00 equiv) in DCM (10 mL), and 4-nitrophenyl chloroformate(237 mg, 1.18 mmol, 1.10 equiv). Triethylamine (324 mg, 3.21 mmol, 3.00equiv) was added. The resulting solution was stirred for 2 h at roomtemperature and concentrated under reduced pressure, as described inExample 1, Step 1 to provide 360 mg (crude) of 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate as a yellow oil. LCMS(ESI, m/z): 327 [M+H]⁺.

Step 2: Preparation of t-butyl4-(3-bromo-4-chlorophenoxy)piperidine-1-carboxylate

A 100-mL round-bottom flask was charged with t-butyl4-hydroxypiperidine-1-carboxylate (2.88 g, 14.3 mmol, 1.50 equiv) andN,N-dimethylformamide (20 mL). The resulting solution was stirred for0.5 h at 0° C. Sodium hydride (574 mg, 14.3 mmol, 1.50 equiv, 60% inmineral oil) was added. The resulting solution was stirred for 0.5 h at0° C. 2-Bromo-1-chloro-4-fluorobenzene (2.00 g, 9.55 mmol, 1.00 equiv)was added. The resulting solution was stirred overnight at roomtemperature and quenched with water (20 mL), as described in Example 19,Step 3. The residue was chromatographed on a silica gel column toprovide 2.62 g (70% yield) of t-butyl4-(3-bromo-4-chlorophenoxy)piperidine-1-carboxylate as a yellow oil.LCMS (ESI, m/z): 390 [M+H]⁺.

Step 3: Preparation of t-butyl4-(4-chloro-3-cyclopentylphenoxy)piperidine-1-carboxylate

A 40-mL vial was charged with t-butyl4-(3-bromo-4-chlorophenoxy)piperidine-1-carboxylate (500 mg, 1.28 mmol,1.00 equiv), bromo(cyclopentyl)zinc (0.77 mL, 3.83 mmol, 3.00 equiv, 0.5M in THF), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(187 mg, 0.260 mmol, 0.20 equiv), copper (I) iodide (48.6 mg, 0.260mmol, 0.20 equiv), and THF (10 mL) under nitrogen. The resultingsolution was stirred overnight at 60° C. and quenched with water (10mL). The resulting solution was extracted with EtOAc (3×15 mL) and theorganic layers were combined, washed with brine (2×15 mL), dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The residue was chromatographed on a silica gel column toprovide 205 mg (42% yield) of t-butyl4-(4-chloro-3-cyclopentylphenoxy)piperidine-1-carboxylate as a yellowoil. LCMS (ESI, m/z): 380 [M+H]⁺.

Step 4: Preparation of 4-(4-chloro-3-cyclopentylphenoxy)piperidine

A flask was charged with t-butyl4-(4-chloro-3-cyclopentylphenoxy)piperidine-1-carboxylate (205 mg, 0.540mmol, 1.00 equiv), DCM (10 mL), and TFA (2 mL). The resulting solutionwas stirred for 3 h at room temperature and concentrated under reducedpressure, as described in Example 1, Step 3 to provide 250 mg (crude) of4-(4-chloro-3-cyclopentylphenoxy)piperidine as a yellow oil. LCMS (ESI,m/z): 280 [M+H]⁺.

Step 5: Preparation ofN-(1-(4-(4-chloro-3-cyclopentylphenoxy)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

A flask was charged with 4-(4-chloro-3-cyclopentylphenoxy)piperidine(150 mg, 0.540 mmol, 1.00 equiv) in DCM (10 mL) and 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate (350 mg, 1.07 mmol, 2.00equiv). DIPEA (209 mg, 1.62 mmol, 3.00 equiv) was added dropwise at 0°C. The resulting solution was stirred 3 h at room temperature andquenched with water (10 mL), as described in Example 2, Step 6. Thecrude product (300 mg) was purified by preparative HPLC to provide 74.7mg (30% yield) ofN-(1-(4-(4-chloro-3-cyclopentylphenoxy)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamideas a yellow solid. ¹H NMR (300 MHz, Chloroform-d) δ 8.03 (d, J=2.7 Hz,1H), 7.22-7.25 (m, 1H), 6.86 (d, J=3.0 Hz, 1H), 6.65-6.69 (m, 1H), 6.30(d, J=2.7 Hz, 1H) 4.55-4.56 (m, 1H), 3.86-3.91 (m, 4H), 3.36-3.38 (m,1H), 3.15 (s, 3H), 1.84-2.11 (m, 6H), 1.70-1.84 (m, 4H), 1.51-1.56 (m,2H). LCMS (ESI, m/z): 489 [M+Na]⁺.

Example 22:N-(1-(4-(4-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-2-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)acetamide

Step 1: Preparation of4-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-2-(trifluoromethyl)benzaldehyde

A round-bottom flask was charged with hexahydro-1H-furo[3,4-c]pyrrole(1.18 g, 10.4 mmol, 2.00 equiv),4-fluoro-2-(trifluoromethyl)benzaldehyde (1.00 g, 5.21 mmol, 1.00equiv), cesium carbonate (3.40 g, 10.4 mmol, 2.00 equiv), and DMF (10mL). The reaction mixture was stirred overnight at 100° C. and quenchedwith water (20 mL). The resulting solution was extracted with EtOAc(3×50 mL) and the organic layers were combined, washed with brine (1×50mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was chromatographed on a silica gel to provide0.800 g (54% yield) of4-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-2-(trifluoromethyl)benzaldehydeas a yellow oil. LCMS (ESI, m/z): 286 [M+H]⁺.

Step 2: Preparation of t-Butyl4-(3-acetamido-1H-pyrazole-1-carbonyl)piperazine-1-carboxylate

A round-bottom flask was charged with triphosgene (334 mg, 1.12 mmol,0.70 equiv) and DCM (10 mL). N-(1H-pyrazol-3-yl)acetamide (302 mg, 2.41mmol, 1.50 equiv) was added at 0° C., followed by DIPEA (830 mg, 6.42mmol, 4.00 equiv). The mixture was stirred for 2 h at 0° C. prior toaddition of t-butyl piperazine-1-carboxylate (300 mg, 1.61 mmol, 1.00equiv). The reaction mixture was stirred overnight at room temperatureand quenched with water (20 mL). The resulting solution was extractedwith DCM (3×20 mL) and the organic layers were combined, washed withbrine (1×20 mL), dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was chromatographed on a silica gelcolumn to provide 420 mg (77% yield) of t-butyl4-(3-acetamido-1H-pyrazole-1-carbonyl)piperazine-1-carboxylate as ayellow solid. LCMS (ESI, m/z): 338 [M+H]⁺.

Step 3: Preparation ofN-(1-(Piperazine-1-carbonyl)-1H-pyrazol-3-yl)acetamide

A round-bottom flask was charged with t-butyl4-(3-acetamido-1H-pyrazole-1-carbonyl)piperazine-1-carboxylate (200 mg,0.590 mmol, 1.00 equiv), DCM (8 mL), and TFA (2 mL). The resultingsolution was stirred overnight at room temperature and concentratedunder reduced pressure to provide 141 mg (quantitative) ofN-(1-(piperazine-1-carbonyl)-1H-pyrazol-3-yl)acetamide as a white oil.LCMS (ESI, m/z): 238 [M+H]⁺.

Step 4: Preparation ofN-(1-(4-(4-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-2-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)acetamide

A round-bottom flask was charged withN-(1-(piperazine-1-carbonyl)-1H-pyrazol-3-yl)acetamide (141 mg, 0.590mmol, 1.20 equiv),4-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-2-(trifluoromethyl)benzaldehyde(141 mg, 0.490 mmol, 1.00 equiv), and DCM (10 mL). The mixture wasstirred for 2 h at room temperature prior to addition of sodiumtriacetoxyborohydride (416 mg, 1.96 mmol, 4.00 equiv). The reactionmixture was stirred overnight at room temperature and quenched withwater (10 mL). The resulting solution was extracted with DCM (3×15 mL)and the organic layers were combined, washed with brine (1×50 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The crude product (260 mg) was purified by preparative HPLC to afford39.7 mg (16% yield) ofN-[1-([4-[(4-[hexahydro-1H-furo[3,4-c]pyrrol-5-yl]-2-(trifluoromethyl)phenyl)methyl]piperazin-1-yl]carbonyl)-1H-pyrazol-3-yl]acetamideas a white solid. ¹H NMR (300 MHz, Chloroform-d) δ 8.01 (d, J=2.7 Hz,1H), 7.71 (br, 1H), 7.53-7.51 (m, 1H), 6.91-6.83 (m, 2H), 6.76-6.73 (m,1H), 4.03-3.96 (m, 2H), 3.81 (br, 4H), 3.70-3.66 (m, 2H), 3.60 (br, 2H),3.51-3.46 (m, 2H), 3.29-3.25 (m, 2H), 3.08-3.02 (m, 2H), 2.53 (br, 4H),2.18 (s, 3H). LCMS (ESI, m/z): 507 [M+H]⁺.

Example 23N-(1-(2-(4-(pyrrolidin-1-yl)-2-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazol-3-yl)acetamide

Step 1: Preparation of4-(pyrrolidin-1-yl)-2-(trifluoromethyl)benzaldehyde

A round-bottom flask was charged with4-fluoro-2-(trifluoromethyl)benzaldehyde (8.00 g, 41.6 mmol, 1.00equiv), pyrrolidine (5.92 g, 83.2 mmol, 2.00 equiv), K₂CO₃ (17.2 g, 124mmol, 3.00 equiv), and DMSO (80 mL) under nitrogen. The reaction mixturewas stirred overnight at 90° C. and quenched with water (100 mL). Theresulting solution was extracted with EtOAc (3×150 mL) and the organiclayers were combined, washed with brine (1×200 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas chromatographed on a silica gel column to provide 6.00 g (59% yield)of 4-(pyrrolidin-1-yl)-2-(trifluoromethyl)benzaldehyde as a yellowsolid. LCMS (ESI, m/z): 244 [M+H]⁺.

Step 2: Preparation ofN-(1-(2-(4-(pyrrolidin-1-yl)-2-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazol-3-yl)acetamide

The title compound was prepared as described in Example 22, Steps 2-4,using t-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate andN-(1H-pyrazol-3-yl)acetamide in Step 2; t-butyl8-(3-acetamido-1H-pyrazole-1-carbonyl)-2,8-diazaspiro[4.5]decane-2-carboxylatein Step 3; andN-(1-(2,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazol-3-yl)acetamide inStep 4 to provide 90.3 mg (40% yield) ofN-[1-[(2-[[4-(pyrrolidin-1-yl)-2-(trifluoromethyl)phenyl]methyl]-2,8-diazaspiro[4.5]decan-8-yl)carbonyl]-1H-pyrazol-3-yl]acetamideas a white solid. ¹H NMR (300 MHz, Chloroform-d) δ 7.97 (d, J=2.7 Hz,1H), 7.73 (br, 1H), 7.49 (br, 1H), 6.86 (d, J=2.7 Hz, 1H), 6.76 (d,J=2.4 Hz, 1H), 6.66 (d, J=8.7 Hz, 1H), 3.71-3.63 (m, 6H), 3.30 (t, J=6.6Hz, 4H), 2.64 (br, 2H), 2.44 (br, 2H), 2.18 (s, 3H), 2.06-2.00 (m, 4H),1.68 (br, 6H). LCMS (ESI, m/z): 519 [M+H]⁺.

Example 24N-(1-(5-(4-Chloro-3-(1-hydroxycyclopentyl)benzyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazol-3-yl)acetamide

Step 1: Preparation of 1-(5-bromo-2-chlorophenyl)cyclopentan-1-ol

A round-bottom flask was charged with 4-bromo-1-chloro-2-iodobenzene(800 mg, 2.52 mmol, 1.00 equiv) and THF (10 mL) under nitrogen.n-Butyllithium (1.01 mL, 2.52 mmol, 1.00 equiv, 2.5 M in hexane) wasadded dropwise at −78° C. The mixture was stirred for 1 h at −78° C.prior to drop-wise addition of cyclopentanone (212 mg, 2.52 mmol, 1.00equiv) over 10 min at −78° C. The reaction mixture was stirred for 1 hat −78° C. and quenched with saturated NH₄Cl solution (30 mL). Theresulting solution was extracted with EtOAc (3×50 mL) and the organiclayers were combined, washed with brine (2×30 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas chromatographed on a silica gel column to provide 400 mg (58% yield)of 1-(5-bromo-2-chlorophenyl)cyclopentan-1-ol as a yellow solid. LCMS(ESI, m/z): 257 [M−OH]⁺.

Step 2: Preparation of 4-chloro-3-(1-hydroxycyclopentyl)benzaldehyde

A round-bottom flask was charged with1-(5-bromo-2-chlorophenyl)cyclopentan-1-ol (400 mg, 1.45 mmol, 1.00equiv) and THF (10 mL) under nitrogen. The mixture was cooled to −78° C.prior to drop-wise addition of n-butyllithium (1.18 mL, 2.90 mmol, 2.00equiv, 2.5 M in hexane) at −78° C. The mixture was stirred for 30 min at−78° C. and DMF (318 mg, 4.35 mmol, 3.00 equiv) was added. The reactionmixture was stirred for 1 h at −78° C. and quenched with saturated NH₄Clsolution (30 mL). The resulting solution was extracted with EtOAc (2×50mL), the organic layers were combined, washed with brine (2×30 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was chromatographed on a silica gel column toprovide 180 mg (55% yield) of4-chloro-3-(1-hydroxycyclopentyl)benzaldehyde as a yellow oil. LCMS(ESI, m/z): 207 [M−OH]⁺.

Step 3: Preparation of 4-nitrophenyl3-acetamido-1H-pyrazole-1-carboxylate

A round-bottom flask was charged with N-(1H-pyrazol-3-yl)acetamide(0.688 g, 5.50 mmol, 1.00 equiv), DCM (25 mL), and TEA (1.67 g, 16.5mmol, 3.00 equiv). 4-Nitrophenyl chloroformate (1.22 g, 6.05 mmol, 1.10equiv) was added at 0° C. The resulting solution was stirred for 1 h at0° C. and concentrated under reduced pressure to provide 1.60 g (crude)of 4-nitrophenyl 3-acetamido-1H-pyrazole-1-carboxylate as yellow oil.LCMS (ESI, m/z): 291 [M+H]⁺.

Step 4: Preparation of t-butyl5-(3-acetamido-1H-pyrazole-1-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

A round-bottom flask was charged with t-butyloctahydropyrrolo[3,4-c]pyrrole-2-carboxylate (1.06 g, 4.99 mmol, 1.00equiv), 4-nitrophenyl 3-acetamido-1H-pyrazole-1-carboxylate (1.60 g,5.51 mmol, 1.10 equiv), TEA (1.52 g, 15.0 mmol, 3.00 equiv), and DCM (20mL). The reaction mixture was stirred for 1 h at room temperature andthen quenched with water (25 mL). The resulting mixture was extractedwith DCM (3×25 mL) and the organic layers were combined, washed withbrine (1×25 mL), dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was chromatographed on a silica gelcolumn to provide 670 mg (37% yield) of t-butyl5-(3-acetamido-1H-pyrazole-1-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylateas a white solid. LCMS (ESI, m/z): 364 [M+H]⁺.

Step 5: Preparation ofN-(1-(octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazol-3-yl)acetamide

round-bottom flask was charged with t-butyl5-(3-acetamido-1H-pyrazole-1-carbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(157 mg, 0.430 mmol, 1.00 equiv), DCM (10 mL), and TFA (2 mL). Theresulting solution was stirred for 2 h at room temperature andconcentrated under reduced pressure to provide 113 mg (quantitative) ofN-(1-(octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazol-3-yl)acetamideas a yellow oil. LCMS (ESI, m/z): 264 [M+H]⁺.

Step 6: Preparation ofN-(1-(5-(4-chloro-3-(1-hydroxycyclopentyl)benzyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazol-3-yl)acetamide

A round-bottom flask was charged withN-(1-(octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazol-3-yl)acetamide(113 mg, 0.430 mmol, 1.20 equiv),4-chloro-3-(1-hydroxycyclopentyl)benzaldehyde (80.0 mg, 0.360 mmol, 1.00equiv), and DCE (15 mL). The mixture was stirred for 1 h at roomtemperature prior to addition of sodium triacetoxyborohydride (305 mg,1.44 mmol, 4.00 equiv). The reaction mixture was stirred overnight atroom temperature and quenched with water (10 mL). The resulting solutionwas extracted with DCM (3×15 mL) and the organic layers were combined,washed with brine (1×20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product (200 mg) waspurified by preparative HPLC to afford 83.2 mg (50% yield) ofN-(1-(5-(4-chloro-3-(1-hydroxycyclopentyl)benzyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-1H-pyrazol-3-yl)acetamideas a white solid. ¹H NMR (300 MHz, Chloroform-d) δ 8.11 (d, J=2.7 Hz,1H), 8.06 (br, 1H), 7.61 (s, 1H), 7.31-7.29 (m, 1H), 7.14-7.11 (m, 1H),6.87 (d, J=2.7 Hz, 1H), 3.98-3.92 (m, 2H), 3.85-3.81 (m, 2H), 3.58 (s,2H), 2.87 (br, 2H), 2.77 (br, 1H), 2.59 (br, 4H), 2.33-2.23 (m, 2H),2.18 (s, 3H), 2.12-2.06 (m, 2H), 1.99-1.92 (m, 2H), 1.90-1.84 (m, 2H).LCMS (ESI, m/z): 472 [M+H]⁺.

Example 251-(3-((8-(3-Acetamido-1H-pyrazole-1-carbonyl)-2,8-diazaspiro[4.5]decan-2-yl)methyl)-5-(trifluoromethyl)phenyl)cyclopentane-1-carboxylicacid

Step 1: Preparation of t-butyl2-(3-bromo-5-(trifluoromethyl)phenyl)acetate

A round-bottom flask was charged with2-(3-bromo-5-(trifluoromethyl)phenyl)acetic acid (12.0 g, 42.4 mmol,1.00 equiv), di-t-butyl dicarbonate (18.6 g, 85.2 mmol, 2.00 equiv), TEA(12.9 g, 127 mmol, 3.00 equiv), and t-BuOH (100 mL). The reactionmixture was stirred overnight at 90° C. and quenched with water (100mL). The resulting solution was extracted with EtOAc (3×150 mL) and theorganic layers were combined, washed with brine (2×100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was chromatographed on a silica gel column to provide 14.0 g(97% yield) of tert-butyl 2-(3-bromo-5-(trifluoromethyl)phenyl)acetateas a colorless liquid. ¹H NMR (400 MHz, Chloroform-d) δ 7.69 (s, 1H),7.65 (s, 1H), 7.50 (s, 1H), 3.59 (s, 2H), 1.47 (s, 9H).

Step 2: Preparation of t-butyl1-(3-bromo-5-(trifluoromethyl)phenyl)cyclopentane-1-carboxylate

A round-bottom flask was charged with t-butyl2-(3-bromo-5-(trifluoromethyl)phenyl)acetate (7.00 g, 20.6 mmol, 1.00equiv), 18-crown-6 (0.273 g, 1.03 mmol, 0.05 equiv), and2-methyltetrahydrofuran (70 mL). Sodium hydride (2.07 g, 60% in mineraloil, 51.7 mmol, 2.50 equiv) was added at 0° C. The mixture was stirredfor 20 min at 0° C. prior to addition of 1,4-dibromobutane (6.65 g, 30.8mmol, 1.50 equiv). The reaction mixture was stirred overnight at roomtemperature and quenched with water (70 mL). The resulting solution wasextracted with EtOAc (3×100 mL) and the organic layers were combined,washed with brine (1×100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was chromatographed ona silica gel column to provide 6.20 g (76% yield) of t-butyl1-(3-bromo-5-(trifluoromethyl)phenyl)cyclopentane-1-carboxylate ascolorless oil. ¹H NMR (300 MHz, Chloroform-d) δ 7.70 (s, 1H), 7.65 (s,1H), 7.56 (s, 1H), 2.65-2.61 (m, 2H), 1.90-1.75 (m, 6H), 1.37 (s, 9H).

Step 3: Preparation of t-butyl1-(3-formyl-5-(trifluoromethyl)phenyl)cyclopentane-1-carboxylate

A round-bottom flask was charged with t-butyl1-(3-bromo-5-(trifluoromethyl)phenyl)cyclopentane-1-carboxylate (6.20 g,15.8 mmol, 1.00 equiv), and THF (50 mL) under nitrogen. n-Butyllithium(8.22 mL, 2.5M in hexane, 20.6 mmol, 1.30 equiv) was added dropwise at−78° C. The resulting solution was stirred for 30 min at −78° C. priorto addition of DMF (5.77 g, 78.9 mmol, 5.00 equiv). The reaction mixturewas stirred for 1 h at −78° C. and quenched with saturated NH₄Clsolution (50 mL). The resulting solution was extracted with EtOAc (3×100mL) and the organic layers were combined, washed with brine (1×100 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was chromatographed on a silica gel column toprovide 3.50 g (65% yield) of t-butyl1-(3-formyl-5-(trifluoromethyl)phenyl)cyclopentane-1-carboxyl ate as acolorless oil. ¹H NMR (300 MHz, Chloroform-d) δ 10.1 (s, 1H), 8.08 (s,1H), 8.03 (s, 1H), 7.90 (s, 1H), 2.75-2.69 (m, 2H), 1.93-1.78 (m, 6H),1.37 (s, 9H).

Step 4: Preparation of t-butyl1-(3-((8-(3-acetamido-1H-pyrazole-1-carbonyl)-2,8-diazaspiro[4.5]decan-2-yl)methyl)-5-(trifluoromethyl)phenyl)cyclopentane-1-carboxylate

The title compound was prepared as described in Example 22, Steps 2-4,using tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate andN-(1H-pyrazol-3-yl)acetamide in Step 2; tert-butyl8-(3-acetamido-1H-pyrazole-1-carbonyl)-2,8-diazaspiro[4.5]decane-2-carboxylatein Step 3; andN-(1-(2,8-diazaspiro[4.5]decane-8-carbonyl)-1H-pyrazol-3-yl)acetamideand tert-butyl1-(3-formyl-5-(trifluoromethyl)phenyl)cyclopentane-1-carboxylate in Step4 to provide 180 mg (67% yield) of tert-butyl1-[3-([8-[(3-acetamido-1H-pyrazol-1-yl)carbonyl]-2,8-diazaspiro[4.5]decan-2-yl]methyl)-5-(trifluoromethyl)phenyl]cyclopentane-1-carboxylateas yellow oil. LCMS (ESI, m/z): 618 [M+H]⁺.

Step 5: Preparation of1-(3-((8-(3-acetamido-1H-pyrazole-1-carbonyl)-2,8-diazaspiro[4.5]decan-2-yl)methyl)-5-(trifluoromethyl)phenyl)cyclopentane-1-carboxylicacid

A round-bottom flask was charged with t-butyl1-(3-((8-(3-acetamido-1H-pyrazole-1-carbonyl)-2,8-diazaspiro[4.5]decan-2-yl)methyl)-5-(trifluoromethyl)phenyl)cyclopentane-1-carboxylate(180 mg, 0.290 mmol, 1.00 equiv), DCM (12 mL), trifluoroacetic acid (3mL). The resulting solution was stirred overnight at room temperatureand concentrated under reduced pressure. The crude product was dissolvedin DCM (15 mL) and the pH value of the solution was adjusted to 8 withsaturated NaHCO₃ solution. The mixture was extracted with DCM (3×20 mL)and the organic layers were combined, washed with brine (2×15 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The crude product (200 mg) was purified by preparative HPLC to afford85.0 mg (52% yield) of1-(3-((8-(3-acetamido-1H-pyrazole-1-carbonyl)-2,8-diazaspiro[4.5]decan-2-yl)methyl)-5-(trifluoromethyl)phenyl)cyclopentane-1-carboxylicacid as a white solid. ¹H NMR (400 MHz, Methanol-d₄) δ 8.00 (d, J=2.8Hz, 1H), 7.72 (s, 1H), 7.65 (s, 1H), 7.55 (s, 1H), 6.78 (d, J=2.8 Hz,1H), 3.98 (br, 2H), 3.91-3.81 (m, 2H), 3.78-3.71 (m, 2H), 2.97 (br, 2H),2.79 (br, 2H), 2.75-2.68 (m, 2H), 2.11 (s, 3H), 1.89-1.86 (m, 3H),1.84-1.77 (m, 3H), 1.75-1.70 (m, 6H). LCMS (ESI, m/z): 562 [M+H]⁺.

Example 26N-(1-(4-((4-Chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzyl)(methyl)amino)-4-methylpiperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

Step 1: Preparation of 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate

A round-bottom flask was charged withN-(1H-pyrazol-3-yl)methanesulfonamide (131 mg, 0.810 mmol, 1.00 equiv),TEA (246 mg, 2.43 mmol, 3.00 equiv), and DCM (10 mL). 4-Nitrophenylchloroformate (180 mg, 0.890 mmol, 1.10 equiv) was added at 0° C. Theresulting solution was stirred for 2 h at room temperature andconcentrated under reduced pressure to provide 264 mg (crude) of4-nitrophenyl 3-methanesulfonamido-1H-pyrazole-1-carboxylate as a yellowoil. LCMS (ESI, m/z): 327 [M+H]⁺.

Step 2: Preparation of4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzaldehyde

A round-bottom flask was charged with 3-bromo-4-chlorobenzaldehyde(0.800 g, 3.65 mmol, 1.00 equiv), hexahydro-1H-furo[3,4-c]pyrrole (0.498g, 4.40 mmol, 1.20 equiv), tris(dibenzylideneacetone)dipalladium (0.168g, 0.180 mmol, 0.05 equiv), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(0.342 g, 0.550 mmol, 0.15 equiv), cesium carbonate (3.59 g, 11.0 mmol,3.00 equiv), and toluene (20 mL) under nitrogen. The reaction mixturewas stirred overnight at 80° C. and quenched with water (30 mL). Theresulting solution was extracted with EtOAc (3×50 mL) and the organiclayers were combined, washed with brine (1×80 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas chromatographed on a silica gel column to provide 0.770 g (84%yield) of4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzaldehyde as ayellow oil. LCMS (ESI, m/z): 252 [M+H]⁺.

Step 3: Preparation of t-butyl4-((4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzyl)amino)-4-methylpiperidine-1-carboxylate

A round-bottom flask was charged with4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzaldehyde (0.400g, 1.59 mmol, 1.00 equiv), tert-butyl4-amino-4-methylpiperidine-1-carboxylate (0.409 g, 1.91 mmol, 1.20equiv), and DCE (15 mL). The mixture was stirred for 1 h at roomtemperature prior to addition of sodium triacetoxyborohydride (1.01 g,4.76 mmol, 3.00 equiv). The reaction mixture was stirred overnight atroom temperature and quenched with water (15 mL). The resulting solutionwas extracted with DCM (3×20 mL) and the organic layers were combined,washed with brine (1×50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was chromatographed ona silica gel column to provide 0.620 g (87% yield) of t-butyl4-((4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzyl)amino)-4-methylpiperidine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 450 [M+H]⁺.

Step 4: Preparation of t-butyl4-((4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzyl)(methyl)amino)-4-methylpiperidine-1-carboxylate

A round-bottom flask was charged with t-butyl4-((4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzyl)amino)-4-methylpiperidine-1-carboxylate(620 mg, 1.38 mmol, 1.00 equiv), paraformaldehyde (621 mg, 20.7 mmol,15.00 equiv), and DCE (15 mL). The mixture was stirred for 1 h at roomtemperature prior to addition of sodium triacetoxyborohydride (878 mg,4.14 mmol, 3.00 equiv). The reaction mixture was stirred overnight at60° C. and quenched with water (20 mL). The resulting solution wasextracted with DCM (3×30 mL) and the organic layers were combined,washed with brine (1×50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was chromatographed ona silica gel column to provide 495 mg (77% yield) of t-butyl4-((4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzyl)(methyl)amino)-4-methylpiperidine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 464 [M+H]⁺.

Step 5: Preparation ofN-(4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzyl)-N,4-dimethylpiperidin-4-amine

A round-bottom flask was charged with t-butyl4-((4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzyl)(methyl)amino)-4-methylpiperidine-1-carboxylate(250 mg, 0.540 mmol, 1.00 equiv), DCM (10 mL), and TFA (2 mL). Theresulting solution was stirred for 2 h at room temperature andconcentrated under reduced pressure to provide 196 mg (quantitative) ofN-(4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzyl)-N,4-dimethylpiperidin-4-amineas a yellow oil. LCMS (ESI, m/z): 364 [M+H]⁺.

Step 6: Preparation ofN-(1-(4-((4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzyl)(methyl)amino)-4-methylpiperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

A round-bottom flask was charged withN-(4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzyl)-N,4-dimethylpiperidin-4-amine(196 mg, 0.540 mmol, 1.00 equiv), 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate (264 mg, 0.810 mmol,1.50 equiv), TEA (164 mg, 1.62 mmol, 3.00 equiv), and DCM (10 mL). Thereaction mixture was stirred for 2 h at room temperature and quenchedwith water (15 mL). The resulting solution was extracted with DCM (3×20mL) and the organic layers were combined, washed with brine (1×50 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude product (400 mg) was purified by preparative HPLC toprovide 150.8 mg (51% yield) ofN-(1-(4-((4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzyl)(methyl)amino)-4-methylpiperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamideas a white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.01 (d, J=2.8 Hz,1H), 7.27-7.25 (m, 1H), 7.00 (br, 1H), 6.91-6.89 (m, 1H), 6.33 (d, J=2.8Hz, 1H), 3.97-3.93 (m, 4H), 3.72-3.69 (m, 4H), 3.50 (s, 2H), 3.38-3.34(m, 2H), 3.11 (s, 5H), 2.97-2.94 (m, 2H), 2.10 (s, 3H), 2.06-1.99 (m,2H), 1.61-1.55 (m, 2H), 1.04 (s, 3H). LCMS (ESI, m/z): 551 [M+H]⁺.

Example 27N-(1-((2R,4R)-4-((4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzyl)(methyl)amino)-2-methylpiperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

Step 1: Preparation of t-butyl(2R,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate

A round-bottom flask was charged with t-butyl(2R)-2-methyl-4-oxopiperidine-1-carboxylate (10.0 g, 46.9 mmol, 1.00equiv) and THF (36 mL). Sodium borohydride (1.07 g, 28.2 mmol, 0.60equiv) was added at 0° C., followed by dropwise addition of MeOH (12mL). The reaction mixture was stirred for 1 h at 0° C. and quenched withwater (50 mL). The resulting solution was extracted with DCM (3×80 mL)and the organic layers were combined, washed with brine (2×100 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude product (11.0 g) was purified by preparative HPLC toprovide 4.90 g (49% yield) of -butyl(2R,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate as a yellow oil. LCMS(ESI, m/z): 216 [M+H]⁺, and 4.10 g (41% yield) of t-butyl(2R,4R)-4-hydroxy-2-methylpiperidine-1-carboxylate as a white solid.LCMS (ESI, m/z): 216 [M+H]⁺.

Step 2: Preparation of t-butyl(2R,4S)-2-methyl-4-((methylsulfonyl)oxy)piperidine-1-carboxylate

A round-bottom flask was charged with t-butyl(2R,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate (300 mg, 1.39 mmol,1.00 equiv), DCM (10 mL), and TEA (423 mg, 4.18 mmol, 3.00 equiv).Methanesulfonyl chloride (239 mg, 2.10 mmol, 1.50 equiv) was added at 0°C., and the reaction mixture was stirred for 2 h at room temperature andquenched with saturated NH₄Cl solution (20 mL). The resulting solutionwas extracted with DCM (3×30 mL) and the organic layers were combined,washed with brine (1×50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to provide 286 mg (70% yield) oft-butyl (2R,4S)-2-methyl-4-((methylsulfonyl)oxy)piperidine-1-carboxylateas a colorless oil. LCMS (ESI, m/z): 294 [M+H]⁺.

Step 3: Preparation of t-butyl(2R,4R)-2-methyl-4-(methylamino)piperidine-1-carboxylate

A round-bottom flask was charged with t-butyl(2R,4S)-2-methyl-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (286mg, 0.970 mmol, 1.00 equiv), ACN (8 mL), and methanamine (8 mL). Thereaction mixture was stirred for 3 days at 60° C. and quenched withwater (15 mL). The resulting solution was extracted with DCM (3×20 mL)and the organic layers were combined, washed with brine (1×50 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The residue was chromatographed on a silica gel column to provide 140 mg(63% yield) of t-butyl(2R,4R)-2-methyl-4-(methylamino)piperidine-1-carboxylate as a yellowoil. LCMS (ESI, m/z): 229 [M+H]⁺.

Step 4: Preparation of t-butyl(2R,4R)-4-((4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzyl)(methyl)amino)-2-methylpiperidine-1-carboxylate

A round-bottom flask was charged with4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzaldehyde(prepared as described in Example 26, Step 2, 154 mg, 0.610 mmol, 1.00equiv), t-butyl (2R,4R)-2-methyl-4-(methylamino)piperidine-1-carboxylate(140 mg, 0.610 mmol, 1.00 equiv), TEA (186 mg, 1.84 mmol, 3.00 equiv),and DCE (10 mL). The mixture was stirred for 1 h at room temperatureprior to addition of sodium triacetoxyborohydride (390 mg, 1.84 mmol,3.00 equiv). The reaction mixture was stirred overnight at roomtemperature and quenched with water (20 mL). The resulting solution wasextracted with DCM (3×30 mL) and the organic layers were combined,washed with brine (1×50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was chromatographed ona silica gel column to provide 210 mg (74% yield) of t-butyl(2R,4R)-4-((4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzyl)(methyl)amino)-2-methylpiperidine-1-carboxylateas yellow oil. LCMS (ESI, m/z): 464 [M+H]⁺.

Step 5: Preparation of(2R,4R)-N-(4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzyl)-N,2-dimethylpiperidin-4-amine

A round-bottom flask was charged with t-butyl(2R,4R)-4-((4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzyl)(methyl)amino)-2-methylpiperidine-1-carboxylate(210 mg, 0.450 mmol, 1.00 equiv), DCM (10 mL), and TFA (2 mL). Theresulting solution was stirred for 2 h at room temperature andconcentrated under reduced pressure to provide 164 mg (quantitative) of(2R,4R)-N-(4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzyl)-N,2-dimethylpiperidin-4-amineas a yellow oil. LCMS (ESI, m/z): 364 [M+H]⁺.

Step 6: Preparation ofN-(1-((2R,4R)-4-((4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzyl)(methyl)amino)-2-methylpiperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

A round-bottom flask was charged with(2R,4R)-N-(4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzyl)-N,2-dimethylpiperidin-4-amine(164 mg, 0.450 mmol, 1.00 equiv), 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate (prepared as describedin Example 26, Stet 1, 221 mg, 0.680 mmol, 1.50 equiv), TEA (137 mg,1.35 mmol, 3.00 equiv), and DCM (10 mL). The reaction mixture wasstirred for 2 h at room temperature and quenched with water (15 mL). Theresulting solution was extracted with DCM (3×20 mL) and the organiclayers were combined, washed with brine (1×50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct (400 mg) was purified by preparative HPLC to provide 23.7 mg(10% yield) ofN-(1-((2R,4R)-4-((4-chloro-3-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)benzyl)(methyl)amino)-2-methylpiperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamideas a white solid. ¹H NMR (400 MHz, MeOH-d₄) δ 8.05 (d, J=2.8 Hz, 1H),7.30 (d, J=8.4 Hz, 1H), 7.10 (s, 1H), 6.98-6.95 (m, 1H), 6.25 (d, J=2.8Hz, 1H), 4.25-4.21 (m, 2H), 4.02-3.99 (m, 2H), 3.67-3.61 (m, 4H),3.47-3.32 (m, 1H), 3.21-3.19 (m, 4H), 3.15 (s, 3H), 3.00-2.92 (m, 2H),2.86-2.80 (m, 1H), 2.35-2.30 (m, 4H), 2.11-2.05 (m, 1H), 1.80-1.73 (m,2H), 1.43 (d, J=6.4 Hz, 3H). LCMS (ESI, m/z): 551 [M+H]⁺.

Example 28N-(14(3aR,5s,6aS)-5-((3-(Trifluoromethyl)benzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

Step 1: Preparation of t-butyl(3aR,5s,6aS)-5-((4-nitrobenzoyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

A round-bottom flask was charged with t-butyl(3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(prepared as described in Example 27, Step 1, using t-butyl(3aR,6a5)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate; 2.27 g,9.99 mmol, 1.00 equiv), 4-nitrobenzoic acid (6.68 g, 40.0 mmol, 4.00equiv), triphenylphosphine (10.5 g, 40.0 mmol, 4.00 equiv) and THF (30mL). Diethyl azodicarboxylate (6.96 g, 40.0 mmol, 4.00 equiv) was addeddropwise at 0° C., and the reaction mixture was stirred overnight atroom temperature under nitrogen atmosphere and quenched by water (50mL). The resulting solution was extracted with EtOAc (3×50 mL) and theorganic layers were combined, washed with water (3×20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was chromatographed on a silica gel column to provide 2.36 g(62% yield) of t-butyl(3aR,5s,6aS)-5-((4-nitrobenzoyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylateas a white solid. LCMS (ESI, m/z): 377 [M+H]⁺.

Step 2: Preparation of t-butyl(3aR,5s,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

A round-bottom flask was charged with t-butyl(3aR,5s,6aS)-5-((4-nitrobenzoyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(2.36 g, 6.27 mmol, 1.00 equiv), MeOH (30 mL), K₂CO₃ (2.60 g, 18.8 mmol,3.00 equiv) and water (5 mL). The reaction mixture was stirred for 3 hat room temperature and concentrated under reduced pressure. Theresulting solution was diluted with water (30 mL), extracted with EtOAc(3×50 mL) and the organic layers were combined, washed with water (3×20mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to provide 1.31 g (crude) of t-butyl(3aR,5s,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate asa white solid. LCMS (ESI, m/z): 228 [M+H]⁺.

Step 3: Preparation of t-butyl(3aR,5s,6aS)-5-((3-(trifluoromethyl)benzyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

A round-bottom flask was charged with t-butyl(3aR,5s,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(681 mg, 3.00 mmol, 1.00 equiv) and DMF (15 mL). Sodium hydride (60% inoil, 400 mg, 10.0 mmol, 2.00 equiv) was added at 0° C., and the reactionmixture was stirred for 0.5 h at room temperature prior to addition of1-(bromomethyl)-3-(trifluoromethyl)benzene (714 mg, 3.00 mmol, 1.00equiv). The resulting solution was stirred overnight at room temperatureand quenched with water (20 mL). The mixture was extracted with EtOAc(3×20 mL) and the organic layers were combined, washed with water (3×20mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was chromatographed on a silica gel columnto provide 680 mg (59% yield) of t-butyl(3aR,5s,6aS)-5-((3-(trifluoromethyl)benzyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylateas a yellow oil. LCMS (ESI, m/z): 386 [M+H]⁺.

Step 4: Preparation of(3aR,5s,6aS)-5-((3-(trifluoromethyl)benzyl)oxy)octahydrocyclopenta[c]pyrrole

A round-bottom flask was charged with t-butyl(3aR,5s,6aS)-5-((3-(trifluoromethyl)benzyl)oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate(116 mg, 0.300 mmol, 1.00 equiv), TFA (2 mL) and DCM (5 mL). Theresulting solution was stirred for 2 h at room temperature andconcentrated under reduced pressure to afford 148 mg (quantitative) of(3aR,5s,6aS)-5-((3-(trifluoromethyl)benzyl)oxy)octahydrocyclopenta[c]pyrroleas a yellow oil. LCMS (ESI, m/z): 286 [M+H]⁺.

Step 5: Preparation ofN-(1-((3aR,5s,6aS)-5-((3-(trifluoromethyl)benzyl)oxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

A vial was charged with(3aR,5s,6aS)-5-((3-(trifluoromethyl)benzyl)oxy)octahydrocyclopenta[c]pyrrole(85.8 mg, 0.300 mmol, 1.00 equiv), TEA (182 mg, 1.80 mmol, 6.00 equiv),4-nitrophenyl 3-(methylsulfonamido)-1H-pyrazole-1-carboxylate (Example26, Step 1; 147 mg, 0.450 mmol, 1.50 equiv) and DCM (15 mL). Thereaction mixture was stirred overnight at room temperature. Theresulting solution was quenched with water (10 mL), extracted with DCM(3×20 mL) and the organic layers were combined, washed with brine (2×20mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was chromatographed on a silica gelcolumn. The crude product was purified by preparative HPLC to afford56.4 mg (40% yield) ofN-(1-((3aR,5s,6aS)-5-((3-(trifluoromethyl)benzypoxy)octahydrocyclopenta[c]pyrrole-2-carbonyl)-1H-pyrazol-3-yl)methanesulfonamideas a white solid. ¹H NMR: (300 MHz, MeOH-d₄) δ 8.14 (d, J=2.7 Hz, 1H),7.69-7.48 (m, 4H), 6.24 (d, J=3.0 Hz, 1H), 4.55 (s, 2H), 4.29-4.19 (m,1H), 4.05-3.68 (m, 4H), 3.12 (s, 3H), 2.99-2.85 (m, 2H), 2.21-2.09 (m,2H), 1.82-1.71 (m, 2H). LCMS (ESI, m/z): 473 [M+H]⁺.

Example 29N-(4-methyl-1-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)piperidin-4-yl)-N-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)glycine

Step 1: Preparation of2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzaldehyde

A round-bottom flask was charged with2-fluoro-4-(trifluoromethyl)benzaldehyde (4.80 g, 25.0 mmol, 1.00equiv), pyrrolidine (5.33 g, 75.0 mmol, 3.00 equiv), DMSO (30 mL), andK₂CO₃ (10.4 g, 75.0 mmol, 3.00 equiv). The reaction mixture was stirredovernight at 80° C. and quenched with water (30 mL). The resultingsolution was extracted with EtOAc (3×50 mL) and the organic layers werecombined, washed with brine (2×50 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waschromatographed on a silica gel column to provide 3.60 g (59% yield) of2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzaldehyde as a brown oil. LCMS(ESI, m/z): 244 [M+H]⁺.

Step 2: Preparation of t-butyl4-methyl-4-((2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate

A round-bottom flask was charged with2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzaldehyde (243 mg, 1.00 mmol,1.00 equiv), t-butyl 4-amino-4-methylpiperidine-1-carboxylate (257 mg,1.20 mmol, 1.20 equiv), MeOH (10 mL), and acetic acid (180 mg, 3.00mmol, 3.00 equiv). The mixture was stirred for 1 h at 60° C. prior toaddition of sodium borohydride (152 mg, 4.00 mmol, 4.00 equiv). Thereaction mixture was stirred overnight at room temperature and quenchedwith water (20 mL). The resulting solution was extracted with DCM (3×30mL) and the organic layers were combined, washed with brine (30 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was chromatographed on a silica gel column toprovide 200 mg (45% yield) of t-butyl4-methyl-4-((2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 442 [M+H]⁺.

Step 3: Preparation of t-butyl4-((2-(tert-butoxy)-2-oxoethyl)(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)amino)-4-methylpiperidine-1-carboxylate

A round-bottom flask was charged with t-butyl4-methyl-4-((2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate(220 mg, 0.500 mmol, 1.00 equiv), t-butyl 2-bromoacetate (116 mg, 0.600mmol, 1.20 equiv), ACN (20 mL), and K₂CO₃ (207 mg, 1.50 mmol, 3.00equiv). The reaction mixture was stirred overnight at 80° C. andquenched with water (20 mL). The resulting solution was extracted withDCM (3×30 mL) and the organic layers were combined, washed with brine(30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was chromatographed on a silica gel columnto provide 130 mg (47% yield) of t-butyl4-((2-(t-butoxy)-2-oxoethyl)(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)amino)-4-methylpiperidine-1-carboxylateas yellow oil. LCMS (ESI, m/z): 556 [M+H]⁺.

Step 4: Preparation ofN-(4-methylpiperidin-4-yl)-N-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)glycine

A 50-mL round-bottom flask was charged with t-butyl4-((2-(t-butoxy)-2-oxoethyl)(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)amino)-4-methylpiperidine-1-carboxylate(130 mg, 0.230 mmol, 1.00 equiv), DCM (10 mL), and TFA (3 mL). Theresulting solution was stirred overnight at room temperature andconcentrated under reduced pressure to provide 93.4 mg (quantitative) ofN-(4-methylpiperidin-4-yl)-N-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)glycineas a yellow oil. LCMS (ESI, m/z): 400 [M+H]⁺.

Step 5: Preparation ofN-(4-methyl-1-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)piperidin-4-yl)-N-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)glycine

A round-bottom flask was charged withN-(4-methylpiperidin-4-yl)-N-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)glycine(93.4 mg, 0.230 mmol, 1.00 equiv), 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate (Example 26, Step 1, 114mg, 0.350 mmol, 1.50 equiv), DCM (10 mL), and TEA (70.9 mg, 0.700 mmol,3.00 equiv). The reaction mixture was stirred overnight at roomtemperature and then quenched with saturated NaHCO₃ solution (10 mL).The resulting solution was extracted with DCM (3×30 mL) and the organiclayers were combined, washed with brine (30 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct (200 mg) was purified by preparative HPLC to afford 10.9 mg (8%)ofN-(4-methyl-1-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)piperidin-4-yl)-N-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)glycineas a white solid. ¹H NMR (300 MHz, Methanol-d₄) δ 8.09 (d, J=3.0 Hz,1H), 7.70 (br, 1H), 7.58 (s, 1H), 7.47 (d, J=8.1 Hz, 1H), 6.28 (d, J=3.0Hz, 1H), 4.71-4.63 (m, 2H), 4.51 (br, 2H), 3.56 (s, 2H), 3.29-3.21 (m,2H), 3.14 (br, 4H), 3.09 (s, 3H), 2.19 (br, 4H), 2.10 (br, 4H), 1.66 (s,3H). LCMS (ESI, m/z): 587 [M+H]⁻.

Example 30N-(1-(4-((3-chloro-4-(4-fluoropiperidin-1-yl)benzyl)oxy)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

Step 1: Preparation of t-butyl4-((4-bromo-3-chlorobenzyl)oxy)piperidine-1-carboxylate

A round-bottom flask was charged with t-butyl4-hydroxypiperidine-1-carboxylate (804 mg, 3.99 mmol, 2.00 equiv) andDMF (10 mL). Sodium hydride (240 mg, 6.00 mmol, 3.00 equiv, 60% inmineral oil) was added at 0° C., and the mixture was stirred for 1 h at0° C. prior to addition of 1-bromo-4-(bromomethyl)-2-chlorobenzene (564mg, 2.00 mmol, 1.00 equiv). The reaction mixture was stirred overnightat room temperature and quenched with water (10 mL). The resultingsolution was extracted with EtOAc (3×15 mL) and the organic layers werecombined, washed with brine (1×20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waschromatographed on a silica gel column to provide 403 mg (50% yield) oft-butyl 4-((4-bromo-3-chlorobenzyl)oxy)piperidine-1-carboxylate as ayellow oil. LCMS (ESI, m/z): 404 [M+H]⁺.

Step 2: Preparation of t-butyl4-((3-chloro-4-(4-fluoropiperidin-1-yl)benzyl)oxy)piperidine-1-carboxylate

A round-bottom flask was charged with t-butyl4-((4-bromo-3-chlorobenzyl)oxy)piperidine-1-carboxylate (403 mg, 1.00mmol, 1.00 equiv), 4-fluoropiperidine (206 mg, 2.00 mmol, 2.00 equiv),tris(dibenzylideneacetone)dipalladium (46.0 mg, 0.0500 mmol, 0.05equiv), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (93.0 mg, 0.150mmol, 0.15 equiv), Cs₂CO₃ (978 mg, 3.00 mmol, 3.00 equiv), and toluene(10 mL) under nitrogen. The reaction mixture was stirred overnight at100° C. and quenched with water (10 mL). The resulting solution wasextracted with DCM (3×15 mL) and the organic layers were combined,washed with brine (1×20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was chromatographed ona silica gel column to provide 170 mg (40% yield) of t-butyl4-((3-chloro-4-(4-fluoropiperidin-1-yl)benzyl)oxy)piperidine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 427 [M+H]⁺.

Step 3: Preparation of1-(2-chloro-4-((piperidin-4-yloxy)methyl)phenyl)-4-fluoropiperidine

A round-bottom flask was charged with t-butyl4-((3-chloro-4-(4-fluoropiperidin-1-yl)benzyl)oxy)piperidine-1-carboxylate(169 mg, 0.397 mmol, 1.00 equiv), DCM (10 mL). N-Methylmorpholine (200mg, 1.98 mmol, 5.00 equiv) was added at 0° C. followed bytrimethyiodosilane (318 mg, 1.59 mmol, 4.00 equiv). The reaction mixturewas stirred for 1 h at 0° C. and quenched with saturated NaHSO₃ solution(10 mL). The resulting solution was extracted with EtOAc (3×20 mL) andthe organic layers were combined, washed with brine (3×10 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressureto provide 120 mg (crude) of1-(2-chloro-4-((piperidin-4-yloxy)methyl)phenyl)-4-fluoropiperidine as ayellow oil. LCMS (ESI, m/z): 327 [M+H]⁺.

Step 4: Preparation ofN-(1-(4-((3-chloro-4-(4-fluoropiperidin-1-yl)benzyl)oxy)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

A round-bottom flask was charged with1-(2-chloro-4-((piperidin-4-yloxy)methyl)phenyl)-4-fluoropiperidine (120mg, 0.368 mmol, 1.00 equiv), 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate (Example 26, Step 1, 180mg, 0.552 mmol, 1.50 equiv), triethylamine (112 mg, 1.11 mmol, 3.00equiv), and DCM (10 mL). The resulting solution was stirred overnight atroom temperature and then quenched with water (20 mL). The mixture wasextracted with DCM (3×20 mL) and the organic layers were combined,washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product (200 mg) waspurified by preparative HPLC to provide 32.6 mg (17% yield) ofN-(1-(4-((3-chloro-4-(4-fluoropiperidin-1-yl)benzyl)oxy)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamideas an off-white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.05 (d, J=2.4Hz, 1H), 7.38 (s, 1H), 7.28-7.21 (m, 1H), 7.06-7.04 (m, 1H), 6.90 (br,1H), 6.33 (d, J=2.4 Hz, 1H), 4.92-4.80 (m, 1H), 4.50 (s, 2H), 4.06-4.02(m, 2H), 3.74-3.71 (m, 1H), 3.65-3.61 (m, 2H), 3.20-3.14 (m, 5H),3.04-2.99 (m, 2H), 2.14-1.96 (m, 6H), 1.84-1.77 (m, 2H). LCMS (ESI,m/z): 514 [M+H]⁺.

Example 31(S)-N-(1-(4-((6-chloro-5-(4-fluoropiperidin-1-yl)pyridin-3-yl)methyl)-3-methylpiperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

Step 1: Preparation of t-butyl(S)-4-(5-bromo-6-chloronicotinoyl)-3-methylpiperazine-1-carboxylate

A round-bottom flask was charged with5-bromo-6-chloropyridine-3-carboxylic acid (2.00 g, 8.47 mmol, 1.00equiv), (S)-t-butyl 3-methylpiperazine-1-carboxylate (1.69 g, 8.47 mmol,1.00 equiv), DIPEA (4.37 g, 33.9 mmol, 4.00 equiv),o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-te-tramethyluroniumhexafluorophosphate (4.83 g, 12.7 mmol, 1.50 equiv) and DMF (20 mL). Theresulting solution was stirred overnight at room temperature andquenched with water (15 mL). The mixture was extracted with EtOAc (3×30mL) and the organic layers were combined, washed with brine (2×30 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was chromatographed on a silica gel column withEtOAc/petroleum ether (⅓) to provide 3.36 g (95% yield) of t-butyl(S)-4-(5-bromo-6-chloronicotinoyl)-3-methylpiperazine-1-carboxylate as ayellow oil. LCMS (ESI, m/z): 418 [M+H]⁺.

Step 2: Preparation of t-butyl(S)-4-((5-bromo-6-chloropyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate

A vial was charged with t-butyl(S)-4-(5-bromo-6-chloronicotinoyl)-3-methylpiperazine-1-carboxylate(1.00 g, 2.39 mmol, 1.00 equiv), borane (1 M in THF, 12.0 mL, 11.9 mmol,5.00 equiv) and THF (15 mL). The resulting solution was stirredovernight at 60° C. and quenched with MeOH (10 mL). The resultingsolution was stirred for 2 hours at 60° C. and concentrated underreduced pressure. The residue was chromatographed on a silica gel columnto provide 0.453 g (47% yield) of t-butyl(S)-4-((5-bromo-6-chloropyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 404 [M+H]⁺.

Step 3: Preparation of t-butyl(S)-4-((6-chloro-5-(4-fluoropiperidin-1-yl)pyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate

A vial was charged with t-butyl(S)-4-((5-bromo-6-chloropyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate(400 mg, 0.988 mmol, 1.00 equiv), 4-fluoropiperidine (206 mg, 1.48 mmol,1.50 equiv), Cs₂CO₃ (966 mg, 2.96 mmol, 3.00 equiv),racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (154 mg, 0.247 mmol0.25 equiv) and toluene (15 mL).Tris(dibenylideneacetone)dipalladium-chloroform (102 mg, 0.0988 mmol,0.10 equiv) was added under nitrogen atmosphere, and the resultingsolution was stirred overnight at 80° C. under nitrogen atmosphere andconcentrated under reduced pressure. The crude product was quenched withwater (10 mL). The mixture was extracted with EtOAc (3×20 mL) and theorganic layers were combined, washed with brine (2×20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was chromatographed on a silica gel column to provide 70 mg (17%yield) of t-butyl(S)-4-((6-chloro-5-(4-fluoropiperidin-1-yl)pyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 427 [M+H]⁻.

Step 4: Preparation of(S)-1-((6-chloro-5-(4-fluoropiperidin-1-yl)pyridin-3-yl)methyl)-2-methylpiperazine

A vial was charged with t-butyl(S)-4-((6-chloro-5-(4-fluoropiperidin-1-yl)pyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate(70.0 mg, 0.164 mmol, 1.00 equiv), TFA (2 mL) and DCM (10 mL). Theresulting solution was stirred for 2 h at room temperature andconcentrated under reduced pressure to provide 53.6 mg (quantitative) of(S)-1-((6-chloro-5-(4-fluoropiperidin-1-yl)pyridin-3-yl)methyl)-2-methylpiperazineas a yellow oil. LCMS (ESI, m/z): 327 [M+H]⁺.

Step 5: Preparation of 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate

A round-bottom flask was charged withN-(1H-pyrazol-3-yl)methanesulfonamide (300 mg, 1.86 mmol, 1.00 equiv),DCM (10 mL) and 4-nitrophenyl chloroformate (452 mg, 2.24 mmol, 1.20equiv). Triethylamine (563 mg, 5.56 mmol, 3.00 equiv) was added dropwiseat 0° C., and the resulting solution was stirred for 2 h at roomtemperature. The mixture was concentrated under reduced pressure toprovide 540 mg (crude) of 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate as a yellow oil. LCMS(ESI, m/z): 327 [M+H]⁻.

Step 6: Preparation of(S)-N-(1-(4-((6-chloro-5-(4-fluoropiperidin-1-yl)pyridin-3-yl)methyl)-3-methylpiperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

A vial was charged with(S)-1-((6-chloro-5-(4-fluoropiperidin-1-yl)pyridin-3-yl)methyl)-2-methylpiperazine(53.6 mg, 0.164 mmol, 1.00 equiv), 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate (80.2 mg, 0.246 mmol,1.50 equiv), TEA (66.3 mg, 0.656 mmol, 4.00 equiv) and DCM (15 mL). Thereaction mixture was stirred overnight at room temperature and quenchedwith water (10 mL). The resulting solution was extracted with DCM (3×20mL) and the organic layers were combined, washed with brine (2×20 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude product was purified by preparative HPLC to afford27.2 mg (32% yield) of(S)-N-(1-(4-((6-chloro-5-(4-fluoropiperidin-1-yl)pyridin-3-yl)methyl)-3-methylpiperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamideas a white solid. ¹H NMR (300 MHz, Methanol-d₄) δ 8.03 (d, J=2.8 Hz,1H), 7.97 (d, J=1.9 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 6.21 (d, J=2.7 Hz,1H), 4.95-4.70 (m, 1H), 4.37-4.09 (m, 2H), 4.08-3.98 (m, 1H), 3.50-3.34(m, 2H), 3.29-3.15 (m, 3H), 3.12 (s, 3H), 3.10-2.99 (m, 2H), 2.83-2.71(m, 1H), 2.71-2.58 (m, 1H), 2.38-2.24 (m, 1H), 2.20-1.92 (m, 4H), 1.19(d, J=6.3 Hz, 3H). LCMS (ESI, m/z): 514 [M+H]⁺.

Example 32(S)-N-(1-(4-(4-chloro-3-(4-isopropoxypiperidin-1-yl)benzyl)-3-methylpiperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

Step 1: Preparation of t-butyl(S)-4-(3-bromo-4-chlorobenzyl)-3-methylpiperazine-1-carboxylate

A round-bottom flask was charged with 3-bromo-4-chlorobenzaldehyde (10.0g, 45.7 mmol, 1.00 equiv), (S)-t-butyl 3-methylpiperazine-1-carboxylate(9.13 g, 45.7 mmol, 1.00 equiv) and DCE (50 mL). The resulting solutionwas stirred for 1 h at room temperature prior to addition of sodiumtriacetoxyborohydride (19.4 g, 91.4 mmol, 2.00 equiv). The reactionmixture was stirred for 2 h at room temperature and quenched with water(20 mL). The resulting solution was extracted with DCM (3×50 mL) and theorganic layers were combined, washed with brine (2×50 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was chromatographed on a silica gel column to provide 9.04 g(49% yield) of t-butyl(S)-4-(3-bromo-4-chlorobenzyl)-3-methylpiperazine-1-carboxylate as ayellow oil. LCMS (ESI, m/z): 403 [M+H]⁺.

Step 2: Preparation of t-butyl(S)-4-(4-chloro-3-(4-hydroxypiperidin-1-yl)benzyl)-3-methylpiperazine-1-carboxylate

A vial was charged with t-butyl(S)-4-(3-bromo-4-chlorobenzyl)-3-methylpiperazine-1-carboxylate (0.500g, 1.24 mmol, 1.00 equiv), piperidin-4-ol (0.188 g, 1.86 mmol, 1.50equiv), Cs₂CO₃ (1.21 g, 3.72 mmol, 3.00 equiv),racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.193 g, 0.310mmol, 0.25 equiv) and toluene (15 mL).Tris(dibenylideneacetone)dipalladium-chloroform (0.128 g, 0.124 mmol,0.10 equiv) was added under nitrogen atmosphere and the resultingsolution was stirred overnight at 80° C. before concentrating underreduced pressure. The crude product was quenched with water (10 mL). Themixture was extracted with EtOAc (3×20 mL) and the organic layers werecombined, washed with brine (2×20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waschromatographed on a silica gel column to provide 0.575 g (crude) oft-butyl(S)-4-(4-chloro-3-(4-hydroxypiperidin-1-yl)benzyl)-3-methylpiperazine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 424 [M+H]⁺.

Step 3: Preparation of t-butyl(S)-4-(4-chloro-3-(4-isopropoxypiperidin-1-yl)benzyl)-3-methylpiperazine-1-carboxylate

A vial was charged with t-butyl(S)-4-(4-chloro-3-(4-hydroxypiperidin-1-yl)benzyl)-3-methylpiperazine-1-carboxylate(243 mg, 0.573 mmol, 1.00 equiv), 2-iodopropane (244 mg, 1.43 mmol, 2.50equiv), silver trifluoromethanesulfonate (368 mg, 1.43 mmol, 2.50 equiv)and DCM (10 mL). The resulting solution was stirred overnight at roomtemperature and quenched with water (10 mL). The mixture was extractedwith DCM (3×20 mL) and the organic layers were combined, washed withbrine (2×20 mL), dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was chromatographed on a silica gelcolumn to provide 121 mg (45% yield) of t-butyl(S)-4-(4-chloro-3-(4-isopropoxypiperidin-1-yl)benzyl)-3-methylpiperazine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 466 [M+H]⁺.

Step 4: Preparation of(S)-N-(1-(4-(4-chloro-3-(4-isopropoxypiperidin-1-yl)benzyl)-3-methylpiperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

The title compound was prepared as described in Example 31, Steps 4-6,using t-butyl(S)-4-(4-chloro-3-(4-isopropoxypiperidin-1-yl)benzyl)-3-methylpiperazine-1-carboxylatein Step 4 to provide(S)-N-(1-(4-(4-chloro-3-(4-isopropoxypiperidin-1-yl)benzyl)-3-methylpiperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamideas a white solid. ¹H NMR (300 MHz, MeOH-d₄) δ 8.04 (d, J=2.9 Hz, 1H),7.33-7.25 (m, 1H), 7.15-7.08 (m, 1H), 7.01-6.94 (m, 1H), 6.22 (d, J=2.8Hz, 1H), 4.38-4.07 (m, 2H), 4.07-3.92 (m, 1H), 3.92-3.74 (m, 1H),3.70-3.51 (m, 1H), 3.51-3.34 (m, 1H), 3.30-3.17 (m, 4H), 3.12 (s, 3H),2.87-2.72 (m, 3H), 2.68-2.55 (m, 1H), 2.32-2.20 (m, 1H), 2.08-1.92 (m,2H), 1.79-1.62 (m, 2H), 1.24-1.10 (m, 9H). LCMS (ESI, m/z): 553 [M+H]⁺.

Example 33(S)-N-(1-(4-((5-(4-fluoropiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-methylpiperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

Step 1: Preparation of potassium(S)-((4-(t-butoxycarbonyl)-2-methylpiperazin-1-yl)methyl)trifluoroborate

A round-bottom flask was charged with t-butyl(3S)-3-methylpiperazine-1-carboxylate (2.00 g, 10.0 mmol, 1.00 equiv),potassium (bromomethyl) trifluoroboranuide (2.01 g, 10.0 mmol, 1.00equiv), and THF (20 mL). The resulting solution was stirred overnight at80° C. and concentrated under reduced pressure. Potassium carbonate(1.38 g, 10.0 mmol, 1.00 equiv) and acetone (15 mL) were added, and theresulting solution was stirred for 2 h at room temperature. The mixturewas dissolved in acetone (2×100 mL) and filtered. The filtered liquorswere combined and concentrated under reduced pressure to provide 2.90 g(91% yield) of potassium(S)-((4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)methyl)trifluoroborateas a yellow solid. LCMS (ESI, m/z): 281 [M−K]⁻.

Step 2: Preparation of5-bromo-3-(4-fluoropiperidin-1-yl)-2-(trifluoromethyl)pyridine

A vial was charged with 5-bromo-3-fluoro-2-(trifluoromethyl)pyridine(400 mg, 1.66 mmol, 1.00 equiv), 4-fluoropiperidine (203 mg, 1.98 mmol,1.20 equiv), K₂CO₃ (681 mg, 4.94 mmol, 3.00 equiv), and DMSO (10 mL).The reaction mixture was stirred for 2 h at 85° C. and quenched withwater (10 mL). The resulting solution was extracted with DCM (3×20 mL)and the organic layers were combined, washed with brine (2×10 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The residue was chromatographed on a silica gel column to provide 140 mg(26% yield) of5-bromo-3-(4-fluoropiperidin-1-yl)-2-(trifluoromethyl)pyridine as ayellow solid. LCMS (ESI, m/z): 327 [M+H]⁺.

Step 3: Preparation of t-butyl(S)-4-((5-(4-fluoropiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate

A vial was charged with5-bromo-3-(4-fluoropiperidin-1-yl)-2-(trifluoromethyl)pyridine (140 mg,0.429 mmol, 1.00 equiv), potassium(S)-((4-(t-butoxycarbonyl)-2-methylpiperazin-1-yl)methyl)trifluoroborate(206 mg, 0.644 mmol, 1.50 equiv),2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (82.0 mg, 0.172mmol, 0.40 equiv), Cs₂CO₃ (420 mg, 1.29 mmol, 3.00 equiv), palladiumacetate (19.0 mg, 0.0860 mmol, 0.20 equiv), 1,4-dioxane (10 mL), andwater (2 mL) under nitrogen. The reaction mixture was stirred for 2 h at80° C. and quenched with water (10 mL). The resulting solution wasextracted with EtOAc (3×20 mL) and the organic layers were combined,washed with brine (2×10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was chromatographed ona silica gel column to provide 130 mg (66% yield) of t-butyl(S)-4-((5-(4-fluoropiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 461 [M+H]⁺.

Step 4: Preparation of(S)-1-((5-(4-fluoropiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methylpiperazine

A round-bottom flask was charged with t-butyl(S)-4-((5-(4-fluoropiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate(130 mg, 0.283 mmol, 1.00 equiv), concentrated hydrochloric acid (1 mL)and 1,4-dioxane (3 mL). The resulting solution was stirred for 2 h atroom temperature and concentrated under reduced pressure to provide 102mg (quantitative) of(S)-1-((5-(4-fluoropiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methylpiperazineas a yellow solid. LCMS (ESI, m/z): 361 [M+H]⁺.

Step 5: Preparation of(S)-N-(1-(4-((5-(4-fluoropiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-methylpiperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

A round-bottom flask was charged withN-(1H-pyrazol-3-yl)methanesulfonamide (68.0 mg, 0.425 mmol, 1.50 equiv),TEA (86.0 mg, 0.849 mmol, 3.00 equiv) and DCM (20 mL). 4-Nitrophenylcarbonochloridate (63.0 mg, 0.311 mmol, 1.10 equiv) was added at 0° C.and the resulting solution was stirred for 2 h at room temperature priorto addition of(S)-1-((5-(4-fluoropiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methylpiperazine(102 mg, 0.283 mmol, 1.00 equiv). The resulting solution was stirred 1 hat room temperature and quenched with water (20 mL). The mixture wasextracted with DCM (3×30 mL) and the organic layers were combined,washed with brine (2×20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product was purified bypreparative HPLC to afford 59.0 mg (38% yield) of(S)-N-(1-(4-((5-(4-fluoropiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-methylpiperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamideas a white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.39 (s, 1H), 8.07(d, J=2.8 Hz, 1H), 7.68 (s, 1H), 7.00 (s, 1H), 6.32 (d, J=2.8 Hz, 1H),5.00-4.92 (m, 0.5H), 4.84-4.82 (m, 0.5H), 4.22-4.19 (m, 2H), 4.07-4.03(m, 1H), 3.50-3.44 (m, 1H), 3.35-3.26 (m, 2H), 3.16-3.13 (m, 5H),2.94-2.91 (m, 2H), 2.75-2.66 (m, 2H), 2.33-2.28 (m, 1H), 2.14-2.00 (m,4H), 1.19 (d, J=6.4 Hz, 3H). LCMS (ESI, m/z): 548 [M+H]⁺.

Example 34N-(1-(4-(2-Chloro-3-(2-hydroxy-2-methylpropoxy)benzyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

Step 1: Preparation of2-chloro-3-(2-hydroxy-2-methylpropoxy)benzaldehyde

A round-bottom flask was charged with 2-chloro-3-hydroxybenzaldehyde(0.624 g, 4.00 mmol, 1.00 equiv), 2,2-dimethyloxirane (0.576 g, 8.00mol, 2.00 equiv), potassium carbonate (1.66 g, 12.0 mmol, 3.00 equiv),and DMSO (10 mL). The reaction mixture was stirred overnight at 80° C.and quenched with water (30 mL). The resulting solution was extractedwith EtOAc (3×40 mL) and the organic layers were combined, washed withbrine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was chromatographed on a silica gelcolumn to provide 550 mg (60% yield) of2-chloro-3-(2-hydroxy-2-methylpropoxy)benzaldehyde as a colorless oil.LCMS (ESI, m/z): 229 [M+H]⁺.

Step 2: Preparation of 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate

A round-bottom flask was charged withN-(1H-pyrazol-3-yl)methanesulfonamide (1.00 g, 6.20 mmol, 1.00 equiv),4-nitrophenyl chloroformate (1.50 g, 7.44 mmol, 1.20 equiv), DCM (20mL), and TEA (1.88 g, 18.6 mmol, 3.00 equiv). The resulting solution wasstirred for 1 h at room temperature and concentrated under reducedpressure to provide 2.02 g (crude) of 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate as a yellow oil. LCMS(ESI, m/z): 327 [M+H]⁺.

Step 3: Preparation of t-butyl4-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)piperazine-1-carboxylate

A round-bottom flask was charged with 4-nitrophenyl3-(methylsulfonamido)-1H-pyrazole-1-carboxylate (2.02 g, 6.19 mmol, 1.00equiv), t-butyl piperazine-1-carboxylate (1.27 g, 6.82 mmol, 1.10equiv), DCM (20 mL), and TEA (1.88 g, 18.6 mmol, 3.00 equiv). Thereaction mixture was stirred overnight at room temperature and quenchedwith water (20 mL). The resulting solution was extracted with DCM (3×40mL) and the organic layers were combined, washed with brine (1×30 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was chromatographed on a silica gel column toprovide 1 g (43% yield) of t-butyl4-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)piperazine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 374 [M+H]⁺.

Step 4: Preparation ofN-(1-(piperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

A round-bottom flask was charged with t-butyl4-(3-(methylsulfonamido)-1H-pyrazole-1-carbonyl)piperazine-1-carboxylate(160 mg, 0.430 mmol, 1.00 equiv), DCM (10 mL), and TFA (2 mL). Theresulting solution was stirred for 2 h at room temperature andconcentrated under reduced pressure to provide 117 mg (quantitative) ofN-(1-(piperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide as ayellow oil. LCMS (ESI, m/z): 274 [M+H]⁺.

Step 5: Preparation ofN-(1-(4-(2-chloro-3-(2-hydroxy-2-methylpropoxy)benzyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

A round-bottom flask was charged withN-(1-(piperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide (117 mg,0.430 mmol, 1.10 equiv),2-chloro-3-(2-hydroxy-2-methylpropoxy)benzaldehyde (88.7 mg, 0.390 mmol,1.00 equiv), and DCM (15 mL). The mixture was stirred for 2 h at roomtemperature prior to addition of sodium triacetoxyborohydride (331 mg,1.56 mmol, 4.00 equiv). The reaction mixture was stirred overnight atroom temperature and quenched with saturated NaHCO₃ solution (20 mL).The resulting solution was extracted with DCM (3×30 mL) and the organiclayers were combined, washed with brine (30 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct (200 mg) was purified by preparative HPLC to provide 20.9 mg(11% yield) ofN-(1-(4-(2-chloro-3-(2-hydroxy-2-methylpropoxy)benzyl)piperazine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamideas a colorless oil. ¹H NMR (300 MHz, Chloroform-d) δ 8.02 (d, J=2.7 Hz,1H), 7.20 (t, J=7.5 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.85 (d, J=7.5 Hz,1H), 6.30 (d, J=2.7 Hz, 1H), 3.85 (br, 6H), 3.68 (s, 2H), 3.13 (s, 3H),2.62-2.59 (m, 4H), 1.39 (s, 6H). LCMS (ESI, m/z): 486 [M+H]⁺.

Example 35N-(1-(4-(cyclopropyl(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

Step 1: Preparation of2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzaldehyde

A round-bottom flask was charged with2-fluoro-4-(trifluoromethyl)benzaldehyde (10.0 g, 52.0 mmol, 1.00equiv), pyrrolidine (7.40 g, 104 mmol, 2.00 equiv), K₂CO₃ (21.7 g, 157mmol, 3.00 equiv), and DMSO (100 mL) under nitrogen. The reactionmixture was stirred overnight at 100° C. and quenched with water (50mL). The resulting solution was extracted with EtOAc (3×50 mL) and theorganic layers were combined, washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was chromatographed on a silica gel column to provide 6.00 g(47% yield) of 2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzaldehyde as ayellow oil. LCMS (ESI, m/z): 244 [M+H]⁺.

Step 2: Preparation of t-butyl4-((2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate

A round-bottom flask was charged with2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzaldehyde (1.12 g, 4.61 mmol,1.00 equiv), t-butyl 4-aminopiperidine-1-carboxylate (1.11 g, 5.53 mmol,1.20 equiv), and DCE (50 mL). The mixture was stirred for 1 h at roomtemperature prior to addition of sodium triacetoxyborohydride (2.93 g,13.8 mmol, 3.00 equiv). The reaction mixture was stirred overnight atroom temperature and quenched with water (50 mL). The resulting solutionwas extracted with DCM (3×80 mL) and the organic layers were combined,washed with brine (2×50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was chromatographed ona silica gel column to provide 1.20 g (61% yield) of t-butyl4-((2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate as a colorless oil. LCMS (ESI,m/z): 428 [M+H]⁺.

Step 3: Preparation of t-butyl4-(cyclopropyl(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate

A round-bottom flask was charged with t-butyl4-((2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate(2.00 g, 4.68 mmol, 1.00 equiv), (1-ethoxycyclopropoxy)trimethylsilane(2.85 g, 16.4 mmol, 3.50 equiv), sodium cyanoborohydride (885 mg, 14.1mmol, 3.00 equiv), acetic acid (2.81 g, 46.8 mmol, 10.00 equiv), THF (60mL), and EtOH (30 mL). The reaction mixture was stirred overnight at 80°C. and quenched with water (50 mL). The resulting solution was extractedwith EtOAc (3×80 mL) and the organic layers were combined, washed withbrine (2×50 mL), dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was chromatographed on a silica gelcolumn to provide 880 mg (40% yield) of t-butyl4-(cyclopropyl(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzypamino)piperidine-1-carboxylateas a yellow oil. LCMS (ESI, m/z): 468 [M+H]⁺.

Step 4: Preparation ofN-cyclopropyl-N-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperidin-4-amine

A round-bottom flask was charged with t-butyl4-(cyclopropyl(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate(400 mg, 0.857 mmol, 1.00 equiv), DCM (10 mL), and TFA (2 mL). Theresulting solution was stirred for 2 h at room temperature andconcentrated under reduced pressure to provide 314 mg (quantitative) ofN-cyclopropyl-N-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperidin-4-amineas a yellow oil. LCMS (ESI, m/z): 368 [M+H]⁺.

Step 5: Preparation ofN-(1-(4-(cyclopropyl(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamide

A round-bottom flask was charged withN-cyclopropyl-N-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperidin-4-amine(314 mg, 0.856 mmol, 1.00 equiv), 4-nitrophenyl3-methanesulfonamido-1H-pyrazole-1-carboxylate (Example 34, Step 2; 335mg, 1.03 mmol, 1.20 equiv), TEA (260 mg, 2.57 mmol, 3.00 equiv), and DCM(10 mL). The reaction mixture was stirred overnight at room temperatureand then quenched with water (20 mL). The resulting solution wasextracted with DCM (3×30 mL) and the organic layers were combined,washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product (200 mg) waspurified by preparative HPLC to afford 219.6 mg (46% yield) ofN-(1-(4-(cyclopropyl(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-1H-pyrazol-3-yl)methanesulfonamideas an off-white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.01 (d, J=2.8Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.26-7.11 (m, 2H), 6.30 (d, J=2.8 Hz,1H), 4.54-4.51 (m, 2H), 3.88 (s, 2H), 3.17-3.12 (m, 7H), 2.90-2.84 (m,2H), 2.72-2.65 (m, 1H), 2.15-2.10 (m, 1H), 2.09-1.92 (m, 4H), 1.87-1.84(m, 2H), 1.78-1.67 (m, 2H), 0.53-0.41 (m, 4H). LCMS (ESI, m/z): 555[M+H]⁺.

Examples 36-226

Examples 36-226 were prepared by similar procedures as described inExamples 1-35.

NMR (¹H NMR, 300 MHz or 400 MHz, MS Ex Name Structure chloroform-d) [M +H]⁺ 36 N-(1-((3aR, 5s,6aS)- 5-((2- Chlorobenzyl) (methyl)amino)octahydro cyclopenta[c] pyrrole-2- carbonyl)-1H- pyrazol-3- yl)acetamide

δ 8.11 (d, J = 2.4 Hz, 1H), 7.75 (br, 1H), 7.47 (br, 1H), 7.30-7.33 (m,1H), 7.14-7.26 (m, 2H), 6.85 (d, J = 2.4 Hz, 1H), 3.95 (br, 2H),3.61-3.74 (m, 4H), 3.18 (br, 1H), 2.82 (br, 2H), 2.16 (s, 6H), 1.85-1.98(m, 4H) 416.2 37 N-(1-((3aR, 5r,6aS)- 5-((2- Chlorobenzyl)(methyl)amino) octahydro cyclopenta[c] pyrrole-2- carbonyl)-1H-pyrazol-3- yl)acetamide

δ 8.11 (d, J = 2.4 Hz, 1H), 7.84 (s, 1H), 7.44-7.45 (m, 1H), 7.24-7.30(m, 1H), 7.13-7.22 (m, 2H), 6.84 (d, J = 2.4 Hz, 1H), 3.79-3.91 (m, 4H),3.63 (s, 2H), 2.96- 2.99 (m, 1H), 2.58-2.69 (m, 2H), 2.13-2.22 (m, 8H),416.2 1.50-1.60 (m, 2H) 38 N-(1-(1-((5- Chloro-1H- indol-2- yl)methyl)-1,8-diazaspiro [4.5]decane-8- carbonyl)-1H- pyrazol-3- yl)acetamide

δ 8.65 (br, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.80-8.00 (m, 1H), 7.48 (m,1H), 7.20-7.25 (m, 1H), 7.00-7.18 (m, 1H), 6.89 ( d, J = 2.7 Hz, 1H),6.25 (s, 1H), 4.42-4.88 (m, 2H), 3.79 (s, 2H), 3.02 (t, J = 2.3 Hz, 2H),2.51- 2.95 (m, 2H), 2.19 455.3 (s, 3H), 1.69-2.02 (m, 6H), 1.41-1.60 (m,2H) 39 N-(1-(1-((5- Chlorobenzo [b]thiophen- 2-yl)methyl)-1,8-diazaspiro [4.5]decane-8- carbonyl)-1H- pyrazol-3- yl)acetamide

δ 8.00 (d, J = 2.7 Hz, 1H), 7.82 (m, 1H), 7.65 (m, 1H), 7.20-7.25 (m,1H), 7.00-7.20 (m, 1H), 6.89 (d, J = 2.7 Hz, 2H), 4.50-4.70 (m, 2H),3.82 (s, 2H), 3.05 (t, J = 2.3 Hz, 2H), 2.76- 2.95 (m, 2H), 2.19 (s,3H), 1.80-2.05 (m, 6H), 1.48-1.60 472.2 (m, 2H) 40 N-(1-(5-(4-(4-Chlorophenoxy) benzyl)octa- hydropyrrolo [3,4-c]pyrrole- 2-carbonyl)-1H-pyrazol-3- yl)methane- sulfonamide

δ 8.16 (d, J = 2.7 Hz, 1H), 7.27-7.30 (m, 3H), 7.25-7.27 (m, 1H),6.91-6.94 (m, 4H), 6.30 (d, J = 2.7 Hz, 1H), 4.04 (br, 2H), 3.75- 3.79(m, 2H), 3.57 (s, 3H), 3.13 (s, 3H), 2.89 (br, 2H), 2.62-2.67 (m, 2H),516.0 2.52-2.54 (m, 2H) 41 N-(1-(5-(3-(4- Chlorophenoxy) benzyl)octa-hydropyrrolo [3,4-c]pyrrole- 2-carbonyl)- 1H-pyrazol-3- yl)methane-sulfonamide

δ 8.14 (d, J = 3.0 Hz, 1H), 7.26-7.30 (m, 3H), 7.05-7.08 (m, 1H), 6.99(s, 1H), 6.84-6.91 (m, 3H), 6.29 (d, J = 3.0 Hz, 1H), 4.03 (br, 2H),3.77 (br, 2H), 3.59 (s, 2H), 516.2 3.12 (s, 3H), 2.88 (br, 2H),2.54-2.67 (m, 4H) 42 (S)-N-(1-(4- (4-Chloro-3- (pyrrolidin-1-yl)benzyl)- 3-methyl- piperazine-1- carbonyl)-1H- pyrazol-3-yl)methane- sulfonamide

δ 8.06 (d, J = 2.4 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.10 (br, 1H) 6.85(s, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.31 (d, J = 2.4 Hz, 1H), 4.27-4.08(m, 2H), 4.06-3.94 (m, 1H), 3.43-3.39 (m, 5H), 3.30-3.13 481.1 (m, 5H),2.86-2.74 (m, 1H), 2.68-2.54 (m, 1H), 2.32-2.16 (m, 1H), 2.03-1.92 (m,4H), 1.20-1.19 (m, 3H) 43 N-(1-(1- ((5,6- Dichloro-1H- indol-2-yl)methyl)-1,8- diazaspiro [4.5]decane- 8-carbonyl)- 1H-pyrazol-3-yl)acetamide

δ 8.03 (d, J = 2.7 Hz, 1H), 7.62-7.78 (m, 1H), 7.60 (s, 1H), 7.33-7.50(m, 1H), 6.89 (d, J = 2.7 Hz, 1H), 6.25 (s, 1H), 4.55-4.72 (m, 2H),3.68-3.98 (m, 2H), 3.00-3.15 (m, 2H), 2.65-2.93 (m, 2H), 2.18 (s, 3H),1.85-2.03 (m, 6H), 1.58-1.72 (m, 511.1 [M + Na]⁺ 2H) 44 N-(1-(5-(4-(4-Chlorophenoxy) benzyl)octa- hydropyrrolo [3,4-c]pyrrole- 2-carbonyl)-1H-pyrazol-3- yl)acetamide

δ 8.14 (d, J = 2.4 Hz, 1H), 7.69 (br, 1H), 7.26-7.30 (m, 3H), 6.88-6.95(m, 5H), 3.60-4.00 (m, 7H), 2.93 (br, 2H), 2.72 (br, 1H), 2.55-2.57 (m,2H), 2.18 (s, 3H) 480.0 45 N-(1-(5-(5- Chloro-2- (trifluoromethyl)benzyl)octa- hydropyrrolo [3,4-c]pyrrole- 2-carbonyl)- 1H-pyrazol-3-yl)methane- sulfonamide

δ 11.3 (br, 1H), 7.70 (s, 2H), 7.52- 7.55 (m, 1H), 7.30-7.32 (m, 1H),6.44 (d, J = 2.4 Hz, 1H), 3.71 (br, 4H), 3.82 (s, 5H), 2.83 (br, 2H),2.58 (br, 2H), 2.47 (br, 2H) 491.9 46 N-(1-(2-(5- Chloro-2-(trifluoromethyl) benzyl)-2,8- diazaspiro[4.5] decane-8- carbonyl)-1H-pyrazol-3-yl) methane- sulfonamide

δ 11.1 (br, 1H), 7.74 (br, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.53- 7.56 (m,1H), 7.29-7.32 (m, 1H), 6.42 (d, J = 2.4 Hz, 1H), 3.72 (br, 2H),3.39-3.59 (m, 4H), 3.26 (s, 3H), 2.63 (br, 2H), 2.40 (br, 2H), 1.66520.0 (br, 2H), 1.51 (br, 4H) 47 N-(1-(5-(4- (Pyrrolidin-1- yl)-2-(trifluoromethyl) benzyl)octa- hydropyrrolo [3,4-c]pyrrole- 2-carbonyl)-1H-pyrazol-3- yl)methane- sulfonamide

δ 11.1 (br, 1H), 7.64 (d, J = 2.7 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H),6.72 (s, 1H), 6.64-6.67 (m, 1H), 6.42 (d, J = 2.7 Hz, 1H), 3.63 (br,4H), 3.24-3.31 (m, 9H), 2.78 (br, 2H), 2.53 (br, 2H), 2.44 (br, 527.02H), 1.95-2.06 (m, 4H) 48 N-(1-(2-(4- (Pyrrolidin-1- yl)-2-(trifluoromethyl) benzyl)-2,8- diazaspiro[4.5] decane-8- carbonyl)-1H-pyrazol-3-yl) methane- sulfonamide

δ 11.6 (br, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H),6.72 (s, 1H), 6.61-6.65 (m, 1H), 6.40 (d, J = 2.4 Hz, 1H), 3.66 (br,2H), 3.38-3.51 (m, 4H), 3.23-3.30 (m, 7H), 2.64 (br, 2H), 2.38 (br, 2H),1.90-2.05 (m, 4H), 1.60 (t, J = 11.7 Hz, 2H), 1.45 (br, 4H) 555.1 492-((8-(3- Acetamido- 1H-pyrazole- 1-carbonyl)- 1,8-diazaspiro[4.5]decan-1- yl)methyl)- 1H-indole-5- carboxylic acid

δ 8.24 (s, 1H), 7.90-8.12 (m, 1H), 7.67-7.89 (m, 1H), 7.20-7.43 (m, 1H),6.66-6.87 (m, 1H), 6.40 (s, 1H), 4.52- 4.68 (m, 2H), 3.86 (s, 2H),3.08-3.24 (m, 2H), 2.80-2.91 (m, 2H), 2.14 (s, 3H), 1.82-2.07 (m, 6H),1.52-1.68 (m, 2H) 487.2 [M + Na]⁺ 50 N-(1-((3aR, 5r,6aS)-5- (Methyl(4-(pyrrolidin- 1-yl)-2- (trifluoromethyl) benzyl)amino) octahydrocyclo-penta[c] pyrrole-2- carbonyl)-1H- pyrazol-3-yl) methane-

δ 8.16 (d, J = 2.7 Hz, 1H), 7.57 (br, 1H), 6.74 (d, J = 2.4 Hz, 1H),6.66- 6.68 (m, 1H), 6.32 (d, J = 2.7 Hz, 1H), 3.99 (br, 2H), 3.60 (br,4H), 3.23-3.32 (m, 4H), 3.19 (s, 4H), 2.86 (br, 2H), 2.14 (br, 3H),1.85-2.06 (m, 8H) 555.1 sulfonamide 51 N-(1-((3aR, 5r,6aS)-5-((5-Chloro-2- (trifluoromethyl) benzyl)(methyl) amino)octa- hydrocyclopenta[c]pyrrole-2- carbonyl)-1H- pyrazol-3- yl)methane- sulfonamide

δ 8.17 (d, J = 2.7 Hz, 1H), 7.86 (br, 1H), 7.53-7.60 (m, 1H), 7.28-7.31(m, 1H), 6.86 (br, 1H), 6.32 (d, J = 2.7 Hz, 1H), 4.01 (br, 2H),3.63-3.88 (m, 4H), 3.14 (s, 4H), 2.87 (br, 2H), 2.15 (s, 3H), 1.86 (br,4H) 520.1 52 N-(1-(4-((6- (Trifluoromethyl) benzo[b] thiophen-2-yl)methyl) piperazine-1- carbonyl)-1H- pyrazol-3-yl) methane- sulfonamide

δ 8.06 (m, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H),7.24- 7.26 (m, 2H), 6.31 (d, J = 2.4 Hz, 1H), 3.89 (br, 6H), 3.15 (s,3H), 2.66 (br, 4H) 488.1 53 N-(1-(1-((6- (Trifluoromethyl) benzo[b]thiophen-2-yl) methyl)-1,8- diazaspiro[4.5] decane-8- carbonyl)-1H-pyrazol-3- yl)methane- sulfonamide

δ 8.03 (s, 2H), 7.75 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H),7.06-7.21 (m, 2H), 6.33 (d, J = 2.4 Hz, 1H), 4.59- 4.61 (m, 2H), 3.96(s, 2H), 3.04-3.13 (m, 5H), 2.85 (s, 2H), 1.87-2.01 (m, 6H), 1.59 (br,2H) 542.0 54 N-(1-(4- (Benzo[b] thiophen-2- ylmethyl) piperazine-1-carbonyl)-1H- pyrazol-3-yl) methane- sulfonamide

δ 8.08-7.97 (m, 1H), 7.87-7.75 (m, 1H), 7.75-7.65 (m, 1H), 7.42-7.23 (m,2H), 7.17 (s, 1H), 6.30 (s, 1H), 3.97- 3.72 (m, 6H), 3.13 (s, 3H),2.69-2.46 (m, 4H), 2.02 (d, J = 1.2 Hz, 1H) 420.0 55 N-(1-(4-((1H-Indol-2-yl) methyl) piperazine-1- carbonyl)- 1H-pyrazol- 3-yl)methane-sulfonamide

δ 8.60 (s, 1H), 8.02 (s, 1H), 7.65-7.48 (m, 1H), 7.41-7.32 (m, 1H),7.22-7.05 (m, 2H), 6.44-6.23 (m, 2H), 3.91-3.77 (m, 4H), 3.71 (s, 2H),3.12 (s, 3H), 2.64-2.48 (m, 4H), 2.03 (s, 1H) 403.1 56 N-(1-(4-(Benzo[d] thiazol-2- ylmethyl) piperazine- 1-carbonyl)- 1H-pyrazol-3-yl)methane- sulfonamide

δ 8.07-7.95 (m, 2H), 7.92-7.84 (m, 1H), 7.53-7.44 (m, 1H), 7.44-7.35 (m,1H), 6.30 (s, 1H), 4.02 (s, 2H), 3.95- 3.79 (m, 4H), 3.14 (s, 3H),2.78-2.62 (m, 4H), 2.02 (s, 1H) 421.0 57 N-(1-(4-((3- Methylbenzo[b]thiophen- 2-yl)methyl) piperazine-1- carbonyl)- 1H-pyrazol-3-yl)methane- sulfonamide

δ 8.04 (s, 1H), 7.86-7.75 (m, 1H), 7.69-7.59 (m, 1H), 7.42-7.30 (m, 2H),6.31 (s, 1H), 3.90- 3.84 (m, 4H), 3.83 (s, 2H), 3.14 (s, 3H), 2.70-2.56(m, 4H), 2.38 (s, 3H), 2.03 (d, J = 0.7 Hz, 1H) 434.1 58 N-(1-(2-(2-(Pyrrolidin- 1-yl)-4- (trifluoromethyl) benzyl)-2,8- diazaspiro[4.5]decane-8- carbonyl)-1H- pyrazol-3-yl) methane- sulfonamide

δ 8.01 (d, J = 3.0 Hz, 1H), 7.53 (br, 1H), 7.09 (br, 2H), 6.31 (d, J =3.0 Hz, 1H), 3.61- 3.79 (m, 6H), 3.22-3.24 (m, 4H), 3.13 (s, 3H), 2.68(br, 2H), 2.50 (br, 2H), 1.93-2.01 (m, 4H), 1.90 (br, 6H) 555.1 59N-(1-(2-(3- Morpholino-5- (trifluoromethyl) benzyl)-2,8- diazaspiro[4.5]decane-8- carbonyl)-1H- pyrazol-3-yl) methane- sulfonamide

δ 8.00 (d, J = 3.0 Hz, 1H), 6.98- 7.03 (m, 3H), 6.30 (d, J = 3.0 Hz,1H), 3.85-3.88 (m, 4H), 3.61-3.78 (m, 6H), 3.19-3.22 (m, 4H), 3.11 (s,3H), 2.66 (br, 2H), 2.45 (br, 2H), 1.69 (br, 6H) 571.1 60 N-(1-(8-(2-(4-Fluoropiperidin- 1-yl)-4- (trifluoromethyl) benzyl)-2,8- diazaspiro[4.5]decane-2- carbonyl)-1H- pyrazol-3-yl) methane- sulfonamide

δ 8.18 (d, J = 2.7 Hz, 1H), 7.57-7.60 (m, 1H), 7.30-7.32 (m, 2H), 6.30(d, J = 2.7 Hz, 1H), 4.72-7.90 (m, 1H), 3.74-3.99 (m, 3H), 3.57 (br,3H), 3.11- 3.15 (m, 5H), 2.83- 2.90 (m, 2H), 2.40- 2.53 (m, 4H), 1.99-2.14 (m, 4H), 1.82- 1.84 (m, 2H), 1.62 587.4 (br, 4H) 61 N-(1-(4-((6-Chloro-2- methyl- pyridin-3-yl) methyl) piperazine-1- carbonyl)-1H-pyrazol-3-yl) methane- sulfonamide

δ 8.00 (d, J = 2.8 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0Hz, 1H), 6.29 (d, J = 2.8 Hz, 1H), 4.46 (s, 1H), 3.82 (t, J = 4.9 Hz,4H), 3.49 (s, 2H), 3.14 (s, 3H), 2.57 (s, 3H), 2.53 (t, 413.1 J = 5.0Hz, 4H) 62 N-(1-(2-(2- Morpholino-4- (trifluoromethyl) benzyl)-2,8-diazaspiro[4.5] decane-8- carbonyl)-1H- pyrazol-3-yl) methane-sulfonamide

δ 8.01 (d, J = 2.7 Hz, 1H), 7.56-7.61 (m, 1H), 7.29-7.34 (m, 2H), 6.31(d, J = 2.7 Hz, 1H), 3.60-3.88 (m, 10H), 3.13 (s, 3H), 3.01 (br, 4H),2.67 (br, 2H), 2.48 (br, 2H), 1.68 (br, 6H) 571.1 63 N-(1-(2-(4-Chloro-2- (pyrrolidin-1- yl)benzyl)-2,8- diazaspiro[4.5] decane-8-carbonyl)-1H- pyrazol-3-yl) methane- sulfonamide

δ 8.00 (d, J = 2.7 Hz, 1H), 7.30-7.32 (m, 1H), 6.80-6.84 (m, 2H), 6.31(d, J = 2.7 Hz, 1H), 3.60-3.79 (m, 6H), 3.20-3.24 (m, 4H), 3.15 (s, 3H),2.66 (br, 2H), 2.45 (br, 2H), 1.90-1.96 (m, 4H), 1.68 (br, 6H) 521.1 64N-(1-(2-(3- (Pyrrolidin-1- yl)-5- (trifluoromethyl) benzyl)-2,8-diazaspiro[4.5] decane-8- carbonyl)-1H- pyrazol-3-yl) methane-sulfonamide

δ 8.00 (d, J = 3.0 Hz, 1H), 6.84 (s, 1H), 6.63-6.68 (m, 2H), 6.30 (d, J= 3.0 Hz, 1H), 3.60-3.78 (m, 6H), 3.28-3.35 (m, 4H), 3.10 (s, 3H), 2.69(br, 2H), 2.46 (br, 2H), 2.00-2.06 (m, 4H), 1.66-1.74 555.1 (m, 6H) 65N-(1-(4-((7- Chloro-3- methyl-1H- indol-2-yl) methyl) piperazine-1-carbonyl)-1H- pyrazol-3-yl) methane- sulfonamide

δ 8.56 (s, 1H), 8.04 (s, 1H), 7.47- 7.37 (m, 1H), 7.20-7.13 (m, 1H),7.08-6.99 (m, 1H), 6.37-6.28 (m, 1H), 4.39 (s, 1H), 3.92- 3.79 (m, 4H),3.69 (s, 2H), 3.13 (s, 3H), 2.68-2.48 (m, 4H), 2.26 (s, 3H) 451.1 66N-(1-(4-((5- Chlorobenzo[b] thiophen-2- yl)methyl) piperazine-1-carbonyl)-1H- pyrazol-3-yl) methane- sulfonamide

δ 7.85 (s, 1H), 7.57-7.43 (m, 2H), 7.13 (s, 1H), 7.17- 6.98 (m, 1H),6.96-6.87 (m, 1H), 6.13 (s, 1H), 3.75- 3.58 (m, 6H), 2.95 (s, 3H), 2.44(t, J = 5.0 Hz, 4H) 454.0 67 N-(1-(4-((4- Chlorobenzo[b] thiophen-2-yl)methyl) piperazine-1- carbonyl)-1H- pyrazol-3-yl) methane-sulfonamide

δ 7.95 (s, 1H), 7.68-7.51 (m, 1H), 7.26-7.23 (m, 2H), 7.18 (s, 1H),7.17- 7.11 (m, 1H), 6.29-6.12 (m, 1H), 3.86-3.68 (m, 6H), 3.04 (s, 3H),2.55 (t, J = 5.0 Hz, 4H) 454.1 68 N-(1-(2-(3- Chloro-5- (pyrrolidin-1-yl)benzyl)- 2,8-diazaspiro [4.5]decane- 8-carbonyl)- 1H-pyrazol-3-yl)methane- sulfonamide

(Methanol-d₄) δ 8.02 (d, J = 2.7 Hz, 1H), 6.65 (s, 1H), 6.49-6.54 (m,2H), 6.23 (d, J = 2.7 Hz, 1H), 3.65-3.87 (m, 6H), 3.26-3.37 (m, 4H),3.13 (s, 3H), 2.90-2.94 (m, 2H), 2.74 (s, 2H), 2.01-2.08 (m, 4H), 521.21.89 (t, J = 6.9 Hz, 2H), 1.67-1.75 (m, 4H) 69 N-(1-(4-(4-Ethynylbenzyl) piperazine-1- carbonyl)-1H- pyrazol-3-yl) methane-sulfonamide

δ 8.03 (d, J = 2.6 Hz, 1H), 7.44-7.47 (m, 2H), 7.27-7.30 (m, 2H), 6.30(d, J = 2.6 Hz, 1H), 3.83 (br, 4H), 3.54 (br, 2H), 2.99-3.12 (m, 4H),2.52 (br, 4H) 387.9 70 N-(1-(4-((3- Chlorobenzo [b]thiophen-2-yl)methyl) piperazine-1- carbonyl)-1H- pyrazol-3-yl) methane-sulfonamide

δ 7.84 (d, J = 2.8 Hz, 1H), 7.65-7.56 (m, 2H), 7.33-7.17 (m, 2H), 6.12(s, 1H), 4.12-3.73 (m, 3H), 3.74-3.64 (m, 4H), 2.95 (s, 3H), 2.55-2.42(m, 4H) 454.0 71 N-(1-(4-((2- (Pyrrolidin- 1-yl)-6- (trifluoromethyl)pyridin-3-yl) methyl) piperazine-1- carbonyl)-1H- pyrazol-3-yl) methane-sulfonamide

δ 8.06 (d, J = 2.7 Hz, 1H), 7.54-7.56 (m, 1H), 7.17 (br, 1H), 6.91-6.93(m, 1H), 6.33 (d, J = 2.7 Hz, 1H), 3.84 (br, 4H), 3.68-3.71 (m, 4H),3.58 (s, 2H), 3.16 (s, 3H) 2.52-2.54 (m, 4H), 1.93-2.03 (m, 4H) 502.4 72N-(1-(2-(4- (Pyrrolidin-1- yl)-3- (trifluoromethyl) benzyl)-2,8-diazaspiro[4.5] decane-8- carbonyl)-1H- pyrazol-3-yl) methane-sulfonamide

δ 7.99 (d, J = 2.7 Hz, 1H), 7.50 (s, 1H), 7.34-7.36 (m, 1H), 6.90-6.93(m, 1H), 6.30 (d, J = 2.7 Hz, 1H), 3.61- 3.76 (m, 6H), 3.30-3.34 (m,4H), 3.10 (s, 3H), 2.70- 2.74 (m, 2H), 2.50 (br, 2H), 1.90-1.99 (m, 4H),1.62-1.76 (m, 6H) 555.5 73 N-(1-(2-(3- (Pyrrolidin-1- yl)-4-(trifluoromethyl) benzyl)-2,8- diazaspiro[4.5] decane-8- carbonyl)-1H-pyrazol-3-yl) methane- sulfonamide

δ 8.00 (d, J = 2.7 Hz, 1H), 7.51-7.53 (m, 1H), 6.97-7.12 (m, 1H),6.77-6.79 (m, 1H), 6.31 (d, J = 2.7 Hz, 1H), 3.67-3.91 (m, 6H), 3.36(br, 5H), 3.13 (s, 3H), 2.54-2.98 (m, 3H), 2.09-2.14 (m, 5H), 1.73-1.97555.1 (m, 5H) 74 N-(1-(2-(2-(3- Oxa-8- azabicyclo [3.2.1]octan- 8-yl)-4-(trifluoromethyl) benzyl)-2,8- diazaspiro[4.5] decane-8- carbonyl)-1H-pyrazol-3-yl) methane-

δ 8.00 (d, J = 2.7 Hz, 1H), 7.61 (br, 1H), 7.12-7.22 (m, 1H), 7.06 (s,1H), 6.32 (d, J = 2.7 Hz, 1H), 3.91-3.94 (m, 2H), 3.61-3.83 (m, 10H),3.20 (s, 3H), 2.76-2.97 (m, 2H), 2.55-2.70 (m, 2H), 1.94-2.07 (m, 4H),1.70-1.90 (m, 6H) 597.1 sulfonamide 75 N-(1-(4- Methyl-4- (methyl(2-(pyrrolidin- 1-yl)-4- (trifluoromethyl) benzyl)amino) piperidine-1-carbonyl)-1H- pyrazol-3-yl) methane-

δ 8.02 (d, J = 2.7 Hz, 1H), 7.80-7.83 (m, 1H), 7.14-7.20 (m, 2H), 6.32(d, J = 2.7 Hz, 1H), 3.99-4.03 (m, 2H), 3.68-3.75 (m, 2H), 3.58 (s, 2H),3.12- 3.18 (m, 7H), 2.09 (s, 3H), 1.94-2.03 (m, 6H), 1.56-1.63 565.2[M + Na]⁺ sulfonamide (m, 2H), 1.25 (s, 3H) 76 4-((2-((4-(3- Acetamido-1H-pyrazole- 1-carbonyl) piperazin-1- yl)methyl)-5- (trifluoromethyl)phenyl)amino) butanoic acid

(Methanol-d₄) δ 8.03 (d, J = 3.2 Hz, 1H), 7.13-7.15 (m, 1H), 6.79-6.84(m, 3H), 3.86 (s, 4H), 3.59 (s, 2H), 3.22 (t, J = 6.8 Hz, 2H), 2.52 (s,4H), 2.45 (t, J = 7.2 Hz, 2H), 2.11 (s, 3H), 1.96-2.02 (m, 2H) 497.1 773-((2-((4-(3- (Methyl- sulfonamido)- 1H-pyrazole- 1-carbonyl)piperazin-1- yl)methyl)-5- (trifluoromethyl) phenyl)amino) propanoicacid

(Methanol-d₄) δ 8.03 (d, J = 2.8 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H),6.82- 6.87 (m, 2H), 6.24 (d, J = 2.8 Hz, 1H), 3.88 (s, 4H), 3.56 (s,2H), 3.42 (t, J = 6.2 Hz, 2H), 3.11 (s, 3H), 2.59 (t, J = 6.2 Hz, 2H),2.47-2.49 (m, 4H) 519.0 78 4-((2-((5-(3- (Methyl- sulfonamido)-1H-pyrazole- 1-carbonyl) hexahydro pyrrolo[3,4-c] pyrrol-2(1H)-yl)methyl)-5- (trifluoromethyl) phenyl)amino) butanoic acid

(Methanol-d₄) δ 8.17 (d, J = 2.7 Hz, 1H), 7.16-7.18 (m, 1H), 6.81-6.85(m, 2H), 6.28 (d, J = 2.7 Hz, 1H), 4.02 (br, 4H), 3.70 (s, 2H),3.12-3.17 (m, 5H), 3.00 (br, 2H), 2.68-2.71 (m, 2H), 2.58-2.63 (m, 2H),2.32 (t, J = 7.0 Hz, 2H), 1.84-1.88 (m, 2H) 559.0 79 4-((2-((8-(3-Acetamido- 1H-pyrazole- 1-carbonyl)- 1,8- diazaspiro [4.5]decan-1-yl)methyl)-5- (trifluoromethyl) phenyl)amino) butanoic acid

(Methanol-d₄) δ 8.05 (d, J = 3.0 Hz, 1H), 7.17-7.20 (m, 1H), 6.79-6.86(m, 3H), 4.60-4.64 (m, 2H), 3.81 (s, 2H), 3.11-3.22 (m, 4H), 2.66 (t, J= 6.9 Hz, 2H), 2.46 (t, J = 7.4 Hz, 2H), 2.15 (s, 3H), 2.05-2.12 (m,6H), 1.82-2.02 (m, 2H), 1.55-1.60 (m, 2H) 551.0 80 N-(1-(4-(2-(Pyrrolidin- 1-yl)-4- (trifluoromethyl) phenoxy) piperidine-1-carbonyl)-1H- pyrazol-3-yl) methane- sulfonamide

δ 8.05 (d, J = 2.7 Hz, 1H), 7.01-7.05 (m, 2H), 6.94 (br, 1H), 6.86-6.88(m, 1H), 6.33 (d, J = 2.7 Hz, 1H), 4.63- 4.68 (m, 1H), 3.98-4.02 (m,2H), 3.79-3.81 (m, 2H), 3.36-3.40 (m, 4H), 3.14 (s, 3H), 2.07- 2.14 (m,2H), 1.92-1.99 (m, 6H) 502.2 81 N-(1-(4-((2- (Pyrrolidin-1-yl)pyridin-3- yl)methyl) piperazine-1- carbonyl)-1H- pyrazol-3-yl)methane- sulfonamide

δ 8.02-8.10 (m, 2H), 7.43-7.46 (m, 1H), 6.58-6.62 (m, 1H), 6.28 (d, J =2.7 Hz, 1H), 3.81 (br, 4H), 3.55-3.61 (m, 4H), 3.52 (s, 2H), 3.13 (s,3H), 2.50 (t, J = 4.8 Hz, 4H), 1.90-1.96 (m, 4H) 434.4 82 N-(1-(4-((3-(Pyrrolidin-1- yl)pyridin-4- yl)methyl) piperazine-1- carbonyl)-1H-pyrazol-3-yl) methane- sulfonamide

δ 8.26 (s, 1H), 8.16 (d, J = 5.1 Hz, 1H), 8.06 (d, J = 2.8 Hz, 1H), 7.40(d, J = 5.1 Hz, 1H), 6.38 (d, J = 2.8 Hz, 1H), 3.91 (br, 4H), 3.58 (s,2H), 3.31 (t, J = 6.6 Hz, 4H), 3.10 (s, 3H), 2.56 (br, 4H), 1.96-2.02(m, 4H) 434.4 83 N-(1-(1-(4- Chloro-3- methylbenzyl)- 1,8-diazaspiro[4.5]decane- 8-carbonyl)- 1H-pyrazol-3- yl)cyclo- propane- carboxamide

δ 8.07 (br, 1H), 7.99 (d, J = 3.0 Hz, 1H), 7.24-7.26 (m, 1H), 7.10-7.18(m, 2H), 6.85 (d, J = 3.0 Hz, 1H), 4.58- 4.62 (m, 2H), 3.56 (br, 2H),3.01-3.10 (m, 2H), 3.56 (br, 2H), 2.35 (s, 3H), 1.83-1.88 (m, 6H),1.53-1.61 (m, 3H), 1.08-1.14 (m, 2H), 0.87-0.92 (m, 2H) 456.1 84N-(1-(1-(4- Chloro-3- methylbenzoyl)- 1,8-diazaspiro [4.5]decane-8-carbonyl)-1H- pyrazol-3-yl) acetamide

δ 8.22 (br, 1H), 7.99 (d, J = 2.7 Hz, 1H), 7.33-7.35 (m, 1H), 7.27-7.28(m, 1H), 7.15-7.18 (m, 1H), 6.86 (d, J = 3.0 Hz, 1H), 4.52- 4.57 (m,2H), 3.43 (t, J = 6.6 Hz, 2H), 3.19-3.29 (m, 2H), 3.02-3.10 (m, 2H),2.38 (s, 3H), 2.19 (s, 3H), 2.07 (t, 444.0 J = 6.8 Hz, 2H), 1.78-1.87(m, 2H), 1.46-1.50 (m, 2H) 85 N-(1-(1-(4- Cyano-3- methylbenzoyl)-1,8-diazaspiro [4.5]decane-8- carbonyl)-1H- pyrazol-3-yl) acetamide

δ 8.00 (d, J = 2.7 Hz, 2H), 7.63 (d, J = 7.8 Hz, 1H), 7.27-7.35 (m, 2H),6.87 (d, J = 2.7 Hz, 1H), 4.56-4.60 (m, 2H), 3.34 (t, J = 6.8 Hz, 2H),3.18-3.26 (m, 2H), 3.03-3.11 (m, 2H), 2.57 (s, 3H), 2.19 (s, 3H),2.08-2.12 (m, 2H), 1.81-1.90 435.1 (m, 2H), 1.48-1.52 (m, 2H) 86N-(1-(4-((3- (Pyrrolidin-1- yl)pyridin-2- yl)methyl) piperazine-1-carbonyl)-1H- pyrazol-3-yl) methane- sulfonamide

δ 8.09-8.10 (m, 1H), 8.04 (d, J = 2.8 Hz, 1H), 7.15- 7.17 (m, 1H),7.09-7.12 (m, 1H), 6.33 (d, J = 2.8 Hz, 1H), 3.85 (br, 4H), 3.78 (s,2H), 3.31 (t, J = 6.8 Hz, 4H), 3.13 (s, 3H), 2.61 (t, J = 4.8 Hz, 4H),1.93-2.01 (m, 4H) 434.2 87 N-(1-(1-(4- Cyano-3- cyclopropyl-benzoyl)-1,8- diazaspiro [4.5]decane- 8-carbonyl)- 1H-pyrazol- 3-yl)acetamide

δ 8.15 (br, 1H), 7.99 (d, J = 2.7 Hz, 1H), 7.60-7.63 (m, 1H), 7.22-7.27(m, 1H), 6.96 (s, 1H), 6.86 (d, J = 2.7 Hz, 1H), 4.54- 4.59 (m, 2H),3.34 (t, J = 6.6 Hz, 2H), 3.21-3.25 (m, 2H), 3.02-3.06 (m, 2H),2.27-2.33 (m, 1H), 2.19 (s, 3H), 2.07 (t, J = 6.8 Hz, 2H), 1.87- 461.21.89 (m, 1H), 1.83-1.84 (m, 1H), 1.48-1.52 (m, 2H), 1.15-1.21 (m, 2H),0.80-0.85 (m, 2H) 88 N-(1-(3- Methyl-4-(2- (pyrrolidin- 1-yl)-4-(trifluoromethyl) benzyl) piperazine-1- carbonyl)-1H- pyrazol-3-yl)methane- sulfonamide

δ 8.04 (d, J = 2.7 Hz, 1H), 7.65-7.67 (m, 1H), 7.13-7.16 (m, 3H), 6.31(d, J = 2.7 Hz, 1H), 3.94-4.16 (m, 3H), 3.34-3.37 (m, 1H), 3.23-3.28 (m,4H), 312-3.21 (m, 5H), 2.70 (br, 2H), 2.27 (br, 1H), 1.89-2.01 (m, 4H),1.14-1.15 (m, 3H) 515.0 89 N-(1-(4-(2- (Cyclopropyl- sulfonyl)-4-(trifluoromethyl) benzyl) piperazine-1- carbonyl)-1H- pyrazol-3-yl)methane- sulfonamide

δ 8.20 (d, J = 2.7 Hz, 1H), 8.05 (br, 1H), 7.77-7.86 (m, 2H), 7.02 (br,1H), 6.33 (br, 1H), 4.10 (s, 2H), 3.83 (br, 4H), 3.23 (br, 1H), 3.14 (s,3H), 2.66 (br, 4H), 1.34-1.40 (m, 2H), 1.02-1.07 (m, 2H) 536.4 90N-(1-(4-((6- Chloro-2- (pyrrolidin-1- yl)pyridin-3- yl)methyl)piperazine-1- carbonyl)-1H- pyrazol-3-yl) methane- sulfonamide

δ 8.04 (d, J = 2.7 Hz, 1H), 7.32-7.34 (m, 1H), 6.55 (d, J = 7.5 Hz, 1H),6.31 (d, J = 2.7 Hz, 1H), 3.82 (br, 4H), 3.64 (br, 4H), 3.50 (br, 2H),3.14 (s, 3H), 2.50 (br, 4H), 1.90-1.94 (m, 4H) 468.0 91 N-(1-(4-Methyl-4- (methyl((2- (pyrrolidin- 1-yl)-6- (trifluoromethyl)pyridin-3-yl) methyl)amino) piperidine-1- carbonyl)-1H- pyrazol-3-yl)methane- sulfonamide

δ 8.02-8.05 (m, 2H), 7.08-7.09 (m, 1H), 7.02 (br, 1H), 6.34 (d, J = 2.7Hz, 1H), 3.99-4.02 (m, 2H), 3.69-3.74 (m, 2H), 3.62 (s, 2H), 3.54 (br,4H), 3.15 (s, 3H), 2.11 (s, 3H), 1.94-2.05 (m, 6H), 1.63-1.65 (m, 2H),1.12 (s, 3H) 544.5 92 N-(1-(4-(2- (3-Oxa-8- azabicyclo [3.2.1]octan-8-yl)-4- (trifluoromethyl) phenoxy) piperidine-1- carbonyl)-1H-pyrazol-3-yl) methane- sulfonamide

δ 8.05-8.09 (m, 1H), 7.05-7.20 (m, 1H), 6.85- 6.95 (m, 2H), 7.01 (s,1H), 6.86-6.97 (m, 1H), 6.35-6.38 (m, 1H), 4.75 (s, 1H), 3.85-4.10 (m,8H), 3.60-3.73 (m, 2H), 3.10 (s, 3H), 1.87-2.21 (m, 8H) 544.0 93N-(5-Chloro-2- (trifluoromethyl) benzyl)-N- ((3aR,5r,6aS)- 2-(3-(methyl-sulfonamido)- 1H-pyrazole-1- carbonyl) octahydro- cyclopenta[c]pyrrol-5-yl) glycine

(Methanol-d₄) δ 8.11-8.14 (m, 2H), 7.63-7.66 (m, 1H), 7.42-7.45 (m, 1H),6.25 (d, J = 2.7 Hz, 1H), 3.98-4.18 (m, 4H), 3.55-3.88 (m, 3H),3.42-3.51 (m, 2H), 3.09 (s, 3H), 2.88 (br, 2H), 1.91-2.05 (m, 4H) 564.194 N-(1-(4- Methyl-4- (methyl(2- morpholino-4- (trifluoromethyl)benzyl)amino) piperidine-1- carbonyl)-1H- pyrazol-3-yl) methane-sulfonamide

δ 8.02 (d, J = 3.0 Hz, 1H), 7.78-7.80 (m, 1H), 7.36-7.38 (m, 1H),7.26-7.30 (m, 1H), 7.01 (br, 1H), 6.32 (d, J = 3.0 Hz, 1H), 3.86- 3.92(m, 6H), 3.65- 3.77 (m, 4H), 3.14 (s, 3H), 2.88-2.91 (m, 4H), 2.01-2.12(m, 3H), 1.97-2.01 (m, 2H), 1.62-1.65 (m, 2H), 1.11 (br, 559.6 3H) 95N-(1-(4-((2- (Pyrrolidin- 1-yl)-6- (trifluoromethyl) pyridin-3-yl)oxy)piperidine- 1-carbonyl)-1H- pyrazol-3-yl) methane- sulfonamide

δ 8.03-8.08 (m, 1H), 7.10-7.30 (m, 1H), 6.85-6.95 (m, 2H), 6.32 (s, 1H),4.54-4.66 (m, 1H), 3.78-4.13 (m, 4H), 3.61-3.76 (m, 4H), 3.11 (s, 3H),2.02- 2.17 (m, 2H), 1.85-2.01 (m, 6H) 503.1 96 N-(1-(4-(2- (1,3,4-Oxadiazol-2- yl)-4- (trifluoromethyl) phenoxy) piperidine-1-carbonyl)-1H- pyrazol-3-yl) methane- sulfonamide

δ 8.65 (s, 1H), 8.25-8.30 (m, 1H), 8.12-8.15 (m, 1H), 7.71-7.80 (m, 1H),7.15-7.20 (m, 2H), 6.30-6.34 (m, 1H), 4.95-5.05 (m, 1H), 4.05-4.25 (m,2H), 3.80-3.95 (m, 2H), 3.05-3.35 (s, 3H), 1.88-2.35 (m, 4H) 523.1 [M +Na]⁺ 97 1-(2-((Methyl (4-methyl-1- (3-(methyl- sulfonamido)-1H-pyrazole- 1-carbonyl) piperidin-4- yl)amino) methyl)-5-(trifluoromethyl) phenyl) pyrrolidine-3- carboxylic acid

(Methanol-d₄) δ 8.05 (d, J = 2.7 Hz, 1H), 7.76-7.79 (m, 1H), 7.32-7.36(m, 2H), 6.25 (d, J = 2.7 Hz, 1H), 3.98-4.15 (m, 4H), 3.74 (br, 2H),3.45-3.47 (m, 1H), 3.24-3.29 (m, 2H), 3.10-3.14 (m, 5H), 2.26-2.29 (m,5H), 2.10 (br, 2H), 1.79-1.89 (m, 2H), 1.33 (s, 3H) 587.2 98 N-(1-(4-(2-(1H-Pyrazol- 1-yl)-4- (trifluoromethyl) phenoxy) piperidine-1-carbonyl)-1H- pyrazol-3-yl) methane- sulfonamide

δ 8.02-8.05 (m, 3H), 7.74 (d, J = 1.5 Hz, 1H), 7.55- 7.58 (m, 1H),7.09-7.17 (m, 2H), 6.47 (t, J = 2.1 Hz, 1H), 6.30 (d, J = 2.7 Hz, 1H),4.76- 4.77 (m, 1H), 3.87-3.91 (m, 2H), 3.63-3.70 (m, 2H), 3.12 (s, 3H),2.01- 2.11 (m, 2H), 499.1 1.89-1.98 (m, 2H) 99 (2-((1-(3- (Methyl-sulfonamido)- 1H-pyrazole- 1-carbonyl) piperidin-4- yl)oxy)-5-(trifluoromethyl) phenyl)glycine

δ 8.05-8.08 (m, 1H), 6.98-7.05 (m, 1H), 6.90-6.95 (m, 1H), 6.68-6.72 (m,1H), 6.25 (s, 1H), 4.80-4.86 (m, 1H), 3.71-4.11 (m, 6H), 3.11 (s, 3H),1.86- 2.18 (m, 4H) 506.2 100 N-(1-(4-(2-(2- Oxopyrrolidin- 1-yl)-4-(trifluoromethyl) phenoxy) piperidine-1- carbonyl)-1H- pyrazol-3-yl)methane- sulfonamide

(Dimethyl sulfoxide-d₆) δ 8.10 (d, J = 2.7 Hz, 1H), 7.63-7.66 (m, 2H),7.40 (d, J = 9.3 Hz, 1H), 6.16 (d, J = 2.7 Hz, 1H), 4.90 (br, 1H),3.76-3.85 (m, 3H), 3.69-3.73 (m, 3H), 3.14 (s, 3H), 2.38-2.43 (m, 2H),2.02-2.15 (m, 4H), 516.2 1.76-1.81 (m, 2H) 101 N-(1-(4-(2- (Pyrrolidine-1-carbonyl)-4- (trifluoromethyl) phenoxy) piperidine-1- carbonyl)-1H-pyrazol-3-yl) methane- sulfonamide

δ 8.03 (d, J = 3.0 Hz, 1H), 7.58-7.61 (m, 2H), 7.34 (s, 1H), 7.04 (d, J= 8.4 Hz, 1H), 6.30 (d, J = 3.0 Hz, 1H), 4.75 (br, 1H), 3.92-3.97 (m,2H), 3.76-3.83 (m, 2H), 3.63-3.67 (m, 2H), 3.23-3.28 (m, 2H), 3.12 (s,3H), 1.85-2.08 (m, 8H) 552.1 [M + Na]⁺ 102 (2-((Methyl(4- methyl-1-(3-(methyl- sulfonamido)- 1H-pyrazole- 1-carbonyl) piperidin-4-yl) amino)methyl)-5- (trifluoromethyl) phenyl)glycine

(Methanol-d₄) δ 8.05 (d, J = 2.7 Hz, 1H), 7.30-7.32 (m, 1H), 6.91-6.93(m, 1H), 6.83 (s, 1H), 6.24 (d, J = 2.7 Hz, 1H), 4.28 (br, 2H), 3.98(br, 2H), 3.82 (s, 2H), 3.48-3.52 (m, 2H), 3.13 (s, 3H), 2.27 (s, 3H),2.10-2.15 (m, 2H), 1.87-1.92 (m, 2H), 1.33 (s, 547.2 3H) 103N-(4-Methyl- 1-(3-(methyl- sulfonamido)- 1H-pyrazole- 1-carbonyl)piperidin-4- yl)-N-(2- (pyrrolidin- 1-yl)-4- (trifluoromethyl) benzyl)acetamide

δ 7.98 (d, J = 2.7 Hz, 1H), 7.35-7.38 (m, 1H), 7.23-7.25 (m, 2H), 7.17(br, 1H), 6.27 (d, J = 2.7 Hz, 1H), 4.53 (s, 2H), 4.20-4.24 (m, 2H),3.15-3.30 (m, 6H), 3.07 (s, 3H), 2.00-2.19 (m, 11H), 1.54 (s, 3H) 593.3[M + Na]⁺ 104 N-(1-(4-((2- (4-(2- Hydroxyacetyl) piperazin- 1-yl)-4-(trifluoromethyl) benzyl)(methyl) amino)-4- methyl- piperidine-1-carbonyl)-1H- pyrazol-3-yl) methane- sulfonamide

δ 8.02 (d, J = 2.7 Hz, 1H), 7.78-7.81 (m, 1H), 7.27-7.42 (m, 2H), 6.32(d, J = 2.7 Hz, 1H), 4.24 (s, 2H), 3.76- 3.90 (m, 6H), 3.68 (br, 2H),3.45 (br, 2H), 3.13 (s, 3H), 2.94 (br, 4H), 2.11 (s, 3H), 1.97-2.01 (m,2H), 1.63-1.67 (m, 2H), 1.12 (s, 3H) 616.6 105 4-(2-((8-(3-Acetamido-1H- pyrazole-1- carbonyl)-1,8- diazaspiro[4.5] decan-1-yl)methyl)-5- chlorophenoxy) butanoic acid

(Methanol-d₄) δ 8.05 (s, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.10 (s, 1H),6.97-7.00 (m, 1H), 6.81 (s, 1H), 4.73- 4.76 (m, 2H), 4.11-4.15 (m, 4H),3.07-3.30 (m, 4H), 2.38-2.43 (m, 2H), 2.22-2.27 (m, 4H), 2.02-2.18 (m,7H), 1.80-1.87 (m, 2H) 518.5 106 4-(2-((4-(3- Acetamido- 1H-pyrazole-1-carbonyl) piperazin-1- yl)methyl)-5- chlorophenoxy) butanoic acid

(Methanol-d₄) δ 8.03-8.04 (m, 1H), 7.29 (d, J = 8.1 Hz, 1H), 6.93-7.02(m, 2H), 6.79 (s, 1H), 3.93-4.08 (m, 2H), 3.76 (br, 4H), 3.68-3.76 (m,2H), 2.77-2.78 (m, 4H), 2.41-2.46 (m, 2H), 2.12 (br, 5H) 464.4 107N-(1-(4-((5- Fluoro-1H- indol-2- yl)methyl) piperazine- 1-carbonyl)-1H-pyrazol- 3-yl) methane- sulfonamide

δ 8.54 (s, 1H), 8.06 (s, 1H), 7.27 (s, 1H), 7.23-7.18 (m, 1H), 6.97-6.86(m, 1H), 6.35 (s, 2H), 3.87 (s, 4H), 3.72 (s, 2H), 3.14 (s, 3H),2.65-2.51 (m, 4H) 421.2 108 (2-((4-(3- Acetamido- 1H-pyrazole-1-carbonyl) piperazin-1- yl)methyl)-5- chlorophenyl) glycine

(Methanol-d₄) δ 8.09 (s, 1H), 6.92- 7.01 (m, 1H), 6.76-6.88 (m, 1H),6.48-6.68 (m, 2H), 3.82-4.01 (m, 6H), 3.64 (s, 2H), 2.52 (bs, 4H), 2.11(s, 3H) 457.3 [M + Na]⁺ 109 N-(1-(4-(3-(4- Fluoropiperidin- 1-yl)-4-(trifluoromethyl) phenoxy) piperidine- 1-carbonyl)- 1H-pyrazol-3-yl)methane- sulfonamide

δ 8.08 (d, J = 2.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 6.72-6.87 (m, 3H),6.34 (d, J = 2.8 Hz, 1H), 4.74-4.95 (m, 1H), 4.65-4.72 (m, 1H), 3.93(br, 4H), 3.48 (s, 3H), 3.12-3.06 (m, 2H), 556.3 [M + Na]⁺ 2.83-2.89 (m,2H), 1.90-2.18 (m, 8H) 110 N-(1-(4-(3- (Cyclopentyl- oxy)-4-(trifluoromethyl) phenoxy) piperidine- 1-carbonyl)- 1H-pyrazol-3-yl)methane- sulfonamide

δ 8.07 (d, J = 2.8 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.15 (s, 1H), 6.53(s, 1H), 6.46-6.49 (m, 1H), 6.34 (d, J = 2.8 Hz, 1H) 4.82-4.85 (m, 1H),4.65-4.69 (m, 1H), 3.89-3.97 (m, 4H), 539.2 [M + Na]⁺ 3.17 (s, 3H),2.05- 2.17 (m, 2H), 1.82-2.01 (m, 8H), 1.64-1.70 (m, 2H) 111 N-(1-(4-(4-Chloro-3- (cyclopentyl- oxy)benzyl) piperazine- 1-carbonyl)-1H-pyrazol-3- yl)methane- sulfonamide

δ 8.04 (d, J = 2.7 Hz, 1H), 7.29 (s, 1H), 6.94-6.96 (m, 2H), 6.80 (d, J= 8.1 Hz, 1H), 6.32 (d, J = 2.7 Hz, 1H), 4.82-4.83 (m, 1H), 3.84 (br,4H), 3.50 (br, 2H), 3.13 (s, 3H), 2.52 482.2 (br, 4H), 1.80-1.89 (m,6H), 1.63-1.65 (m, 2H) 112 N-(1-(5-(3- (Trifluoro- methyl) benzyl)octa-hydropyrrolo [3,4-c]pyrrole- 2-carbonyl)- 1H-pyrazol-3- yl)acetamide

δ 8.14 (d, J = 2.7 Hz, 1H), 7.79 (br, 1H), 7.40-7.57 (m, 4H), 6.88 (d, J= 2.7 Hz, 1H), 4.00- 4.03 (m, 2H), 3.76-3.80 (m, 2H), 3.65 (s, 2H), 2.88(br, 2H), 2.52-2.67 (m, 4H), 2.18 (s, 3H) 422.2 113 N-(1-(5-(3-(Trifluoro- methoxy) benzyl)octa- hydropyrrolo [3,4-c]pyrrole-2-carbonyl)- 1H-pyrazol-3- yl)acetamide

δ 8.14 (d, J = 2.7 Hz, 1H), 7.90 (br, 1H), 7.32 (t, J = 7.8 Hz, 1H),7.19- 7.25 (m, 2H), 7.10 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 2.7 Hz, 1H),4.02-4.04 (m, 2H), 3.75-3.78 (m, 2H), 3.61 (s, 2H), 2.87 438.4 (br, 2H),2.52-2.64 (m, 4H), 2.18 (s, 3H) 114 N-(1-(5-(3- (Trifluoro- methyl)benzyl)octa- hydropyrrolo [3,4-c]pyrrole- 2-carbonyl)- 1H-pyrazol-3-yl)methane- sulfonamide

δ 8.16 (d, J = 2.7 Hz, 1H), 7.49-7.56 (m, 3H), 7.42 (t, J = 7.5 Hz, 1H),6.31 (d, J = 2.7 Hz, 1H), 4.04 (br, 2H), 3.75-3.79 (m, 2H), 3.65 (s,2H), 3.13 (s, 3H), 2.90 (br, 2H), 2.54-2.66 (m, 4H) 458.2 115N-(1-(5-(3- (Trifluoro- methoxy) benzyl)octa- hydropyrrolo[3,4-c]pyrrole- 2-carbonyl)- 1H-pyrazol-3- yl)methane- sulfonamide

δ 8.15-8.16 (m, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.18- 7.24 (m, 2H), 7.09(d, J = 8.1 Hz, 1H), 6.28-6.29 (m, 1H), 4.03 (br, 2H), 3.75-3.79 (m,2H), 3.62 (s, 2H), 3.13 (s, 3H), 2.89 474.1 (br, 2H), 2.53-2.66 (m, 4H)116 N-(1-(4-(3- (1,3,4- Oxadiazol- 2-yl)-4- (trifluoro- methyl)benzyl)piperazine- 1-carbonyl)- 1H-pyrazol-3- yl)methane- sulfonamide

δ 8.62 (s, 1H), 8.05-8.07 (m, 2H), 7.86 (d, J = 8.0 Hz, 1H), 7.71 (d, J= 8.0 Hz, 1H), 7.43 (br, 1H), 6.32 (d, J = 2.8 Hz, 1H), 3.87 (br, 4H),3.68 (s, 2H), 3.16 (s, 3H), 2.58 (t, J = 4.8 Hz, 4H) 522.2 [M + Na]⁺ 117(S)-N-(1-(4- (4-Chloro-3- (3-fluoro- pyrrolidin- 1-yl)benzyl)piperazine- 1-carbonyl)- 1H-pyrazol- 3-yl)methane- sulfonamide

δ 8.05 (d, J = 2.8 Hz, 1H), 7.27-7.28 (m, 1H), 6.91 (br, 1H), 6.79-6.81(m, 1H), 6.32 (d, J = 2.8 Hz, 1H), 5.26- 5.42 (m, 1H), 3.87-4.06 (m,5H), 3.64-3.70 (m, 1H), 3.45-3.55 (m, 3H), 3.32-3.37 (m, 1H), 3.14 (s,3H), 2.56 485.4 (br, 4H), 2.10- 2.32 (m, 2H) 118 4-(((3R,4S)- 1-(3-Acetamido- 1H-pyrazole- 1-carbonyl)- 3-fluoro- piperidin-4- yl)oxy)-2-(trifluoromethyl) benzamide

δ 8.05 (d, J = 2.8 Hz, 1H), 7.84 (br, 1H), 7.60 (d, J = 8.4 Hz, 1H),7.30 (s, 1H), 7.15-7.19 (m, 1H), 6.92 (d, J = 2.8 Hz, 1H), 5.83 (br,2H), 4.72-4.98 (m, 2H), 4.25-4.34 (m, 1H), 3.95-4.17 (m, 2H), 458.43.79-3.83 (m, 1H), 2.20-2.27 (m, 4H), 1.97-2.05 (m, 1H) 119 (S)-N-(1-(4-(3-(3-Fluoro- pyrrolidin-1- yl)-4- (trifluoromethyl) benzyl)piperazine-1- carbonyl)-1H- pyrazol-3- yl)methane- sulfonamide

δ 8.04 (d, J = 3.0 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.02 (s, 1H), 6.90(d, J = 8.1 Hz, 1H), 6.31 (d, J = 3.0 Hz, 1H), 5.22-5.42 (m, 1H),3.81-3.85 (m, 4H), 3.31-3.74 (m, 6H), 3.13 (s, 3H), 2.54 (br, 4H),2.05-2.33 519.2 (m, 2H) 120 (R)-N-(1-(4- (3-(3-Fluoro- pyrrolidin-1-yl)-4- (trifluoromethyl) benzyl) piperazine-1- carbonyl)-1H- pyrazol-3-yl)methane- sulfonamide

δ 8.04 (d, J = 2.7 Hz, 1H), 7.53-7.56 (m, 1H), 7.03 (br, 1H), 6.89-6.91(m, 1H), 6.32 (d, J = 2.7 Hz, 1H), 5.22- 5.42 (m, 1H), 3.82-3.87 (m,4H), 3.31-3.74 (m, 6H), 3.13 (s, 3H), 2.56 (br, 4H), 2.05-2.33 (m, 2H)519.5 121 N-(1-(5-(4- (Pyrrolidin- 1-yl)-2- (trifluoromethyl)benzyl)octa- hydropyrrolo [3,4-c]pyrrole- 2-carbonyl)- 1H-pyrazol-3-yl)acetamide

δ 8.16 (d, J = 2.8 Hz, 1H), 7.84 (br, 1H), 7.46-7.49 (m, 1H), 6.89 (s,1H), 6.76 (s, d, J = 2.8 Hz, 1H), 6.64-6.67 (m, 1H), 4.11 (br, 2H),3.72-3.74 (m, 2H), 3.67 (s, 2H), 3.29-3.33 (m, 4H), 2.87 (br, 2H), 491.52.57-2.64 (m, 4H), 2.20 (s, 3H), 2.01- 2.07 (m, 4H) 122 (R)-N-(1-(4-(4-Chloro- 3-(3-fluoro- pyrrolidin- 1-yl)benzyl) piperazine-1-carbonyl)- 1H-pyrazol- 3-yl)methane- sulfonamide

δ 8.04 (d, J = 2.7 Hz, 1H), 7.24-7.26 (m, 1H), 6.89 (br, 1H), 6.76-6.80(m, 1H), 6.32 (d, J = 2.7 Hz, 1H), 5.22- 5.41 (m, 1H), 4.01-4.07 (m,1H), 3.70-3.95 (m, 4H), 3.61-3.68 (m, 1H), 3.42-3.55 (m, 3H), 3.30-3.36(m, 1H), 485.4 3.13 (s, 3H), 2.54 (br, 4H), 2.01- 2.31 (m, 2H) 1234-((4-(3- Acetamido- 1H-pyrazole- 1-carbonyl) piperazin-1- yl)methyl)-2-(trifluoromethyl) benzamide

(Methanol-d₄) δ 8.05 (d, J = 2.8 Hz, 1H), 7.79 (s, 1H), 7.70 (d, J = 7.6Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 2.8 Hz, 1H), 3.89 (s,4H), 3.70 (s, 2H), 439.4 2.57-2.59 (m, 4H), 2.13 (s, 3H) 124 4-((5-(3-Acetamido- 1H-pyrazole- 1-carbonyl) hexahydro pyrrolo [3,4-c]pyrrol-2(1H)-yl) methyl)-2- (trifluoromethyl)

(Methanol-d₄) δ 8.14 (d, J = 2.8 Hz, 1H), 7.73 (s, 1H), 7.66 (d, J = 8.0Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 6.82 (d, J = 2.8 Hz, 1H), 3.91-3.99(m, 4H), 3.72 (s, 2H), 465.5 benzamide 2.94-2.95 (m, 2H), 2.69-2.71 (m,2H), 2.55-2.57 (m, 2H), 2.14 (s, 3H) 125 4-((8-(3- Acetamido-1H-pyrazole- 1-carbonyl)- 2,8- diazaspiro [4.5]decan-2- yl)methyl)-2-(trifluoromethyl) benzamide

(Methanol-d₄) δ 8.02 (d, J = 2.8 Hz, 1H), 7.77 (s, 1H), 7.68 (d, J = 8.0Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 2.8 Hz, 1H), 3.80-3.84(m, 2H), 3.69-3.71 (m, 4H), 2.67-2.71 (m, 2H), 2.52 (s, 2H), 2.14 (s,3H), 1.76-1.80 493.5 (m, 2H), 1.68-1.73 (m, 4H) 126 4-((7-(3- Acetamido-1H-pyrazole- 1-carbonyl)- 2,7-diazaspiro [3.5]nonan-2- yl)methyl)-2-(trifluoromethyl) benzamide

(Methanol-d₄) δ 8.01 (d, J = 3.0 Hz, 1H), 7.73 (s, 1H) 7.64 (d, J = 7.8Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 2.7 Hz, 1H), 3.72-3.81(m, 6H), 3.20 479.5 (s, 4H), 2.14 (s, 3H), 1.89- 1.92 (m, 4H) 127N-(1-(4-(3- (Trifluoromethyl) benzyl) piperazine-1- carbonyl)-1H-pyrazol-3- yl)acetamide

δ 8.01 (d, J = 2.7 Hz, 1H), 7.72 (br, 1H), 7.60 (s, 1H), 7.52-7.54 (m,2H), 7.42-7.47 (m, 1H), 6.87 (d, J = 2.7 Hz, 1H), 3.85 (br, 4H), 3.59(s, 2H), 2.51-2.54 (m, 4H), 2.17 (s, 3H) 396.5 128 N-(1-(4-(3-(Trifluoro- methoxy) benzyl) piperazine- 1-carbonyl)- 1H-pyrazol-3-yl)acetamide

δ 8.01 (d, J = 2.7 Hz, 1H), 7.77 (br, 1H), 7.32-7.38 (m, 1H), 7.23-7.24(m, 1H), 7.11-7.14 (m, 1H), 6.87 (d, J = 2.7 Hz, 1H), 3.86 (br, 4H),3.56 (s, 2H), 2.51-2.54 (m, 4H), 2.17 (s, 3H) 412.5 129 N-(1-(4-(2-Methyl-3- (trifluoromethyl) benzyl) piperazine-1- carbonyl)-1H-pyrazol-3- yl)acetamide

δ 8.01 (d, J = 2.7 Hz, 1H), 7.70 (br, 1H), 7.56-7.61 (m, 1H), 7.43-7.45(m, 1H), 7.21-7.24 (m, 1H), 6.88 (d, J = 2.7 Hz, 1H), 3.82 (br, 4H),3.55 (br, 2H), 2.49-2.53 (m, 7H), 2.18 (s, 3H) 410.5 130 4-(((1-(3-Acetamido- 1H-pyrazole- 1-carbonyl)- 4-methyl- piperidin-4- yl)(methyl)amino) methyl)-2- (trifluoromethyl)

(Methanol-d₄) δ 8.02 (d, J = 2.8 Hz, 1H), 7.74 (s, 1H), 7.70 (d, J = 8.0Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 2.8 Hz, 1H), 3.85-3.91(m, 2H), 3.79-3.82 (m, 2H), 3.72 (s, 2H), 2.11- 481.5 benzamide 2.12 (m,6H), 2.01-2.05 (m, 2H), 1.63-1.70 (m, 2H), 1.12 (s, 3H) 131 N-(1-(4-((3-Methyl-[1,1′- biphenyl]-4- yl)methyl) piperazine- 1-carbonyl)-1H-pyrazol-3- yl)acetamide

δ 8.02 (d, J = 2.7 Hz, 1H), 7.74 (br, 1H), 7.57-7.60 (m, 2H), 7.41-7.46(m, 3H), 7.26-7.38 (m, 3H), 6.89 (d, J = 2.7 Hz, 1H), 3.84 (br, 4H),3.57 (br, 2H), 2.58 (br, 4H), 2.44 (s, 3H), 2.18 (s, 418.5 3H) 1321-(3-(((1-(3- Acetamido- 1H-pyrazole- 1-carbonyl)- 4-methyl-piperidin-4- yl)(methyl) amino) methyl)-5- (trifluoromethyl)phenyl)cyclo- pentane-1-

(Methanol-d₄) δ 8.02 (d, J = 2.7 Hz, 1H), 7.71 (s, 1H), 7.56 (s, 1H),7.52 (s, 1H), 6.79 (d, J = 2.7 Hz, 1H), 3.83-3.92 (m, 4H), 3.78 (s, 2H),2.66-2.70 (m, 2H), 2.20 (s, 3H), 2.12 (s, 3H), 2.02-2.07 (m, 2H),1.83-1.89 572.2 [M + Na]⁺ carboxylic acid (m, 2H), 1.68-1.76 (m, 6H),1.18 (s, 3H) 133 N-(1-((3R)-4- (4-Chloro-3- (tetrahydro- 1H-furo[3,4-c]pyrrol-5(3H)- yl)benzyl)-3- methyl- piperazine- 1-carbonyl)-1H-pyrazol-3- yl)methane-

δ 8.05 (d, J = 2.8 Hz, 1H), 7.12-7.29 (m, 1H), 7.03 (br, 1H), 6.90-6.95(m, 2H), 6.32 (d, J = 2.8 Hz, 1H), 4.17 (br, 2H), 3.96-4.02 (m, 3H),3.68-3.71 (m, 2H), 3.42 (br, 1H), 3.31-3.35 (m, 2H), 3.15-3.20 (m, 523.5sulfonamide 7H), 2.98-3.03 (m, 2H), 2.74-2.77 (m, 1H), 2.61 (br, 1H),2.21-2.25 (m, 1H), 1.19 (d, J = 5.2 Hz, 3H) 134 N-(1-((3R,4S)-3-Fluoro-4- (3-(4-fluoro- piperidin-1- yl)-4- (trifluoromethyl) phenoxy)piperidine-1- carbonyl)-1H- pyrazol-3-yl)

δ 8.07 (d, J = 2.8 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.03 (br, 1H),6.88-6.95 (m, 1H), 6.70-6.81 (m, 1H), 6.33 (d, J = 2.8 Hz, 1H),4.86-5.05 (m, 1H), 4.60-4.86 (m, 2H), 4.30-4.50 551.9 methane- (m, 1H),3.87-4.16 sulfonamide (m, 2H), 3.62-3.79 (m, 1H), 3.17 (s, 3H),3.00-3.13 (m, 2H), 2.77-2.90 (m, 2H), 2.15-2.32 (m, 1H), 1.89-2.15 (m,5H) 135 N-(1-((2S)-4- (4-Chloro-3- (tetrahydro- 1H-furo [3,4-c]pyrrol-5(3H)-yl) benzyl)-2- methyl- piperazine-1- carbonyl)-1H- pyrazol-3-yl)

δ 8.05 (d, J = 2.8 Hz, 1H), 7.28 (s, 1H), 6.89-7.01 (m, 3H), 6.32 (d, J= 2.8 Hz, 1H), 4.71 (br, 1H), 4.35- 4.38 (m, 1H), 4.01-4.04 (m, 2H),3.69-3.71 (m, 2H), 3.28-3.55 (m, 5H), 3.15-3.27 (m, 5H), 523.5 methane-2.88-2.99 (m, 3H), sulfonamide 2.70 (br, 1H), 2.25 (br, 2H), 1.47 (d, J= 5.2 Hz, 3H) 136 (S)-N-(1-(4- (4-Chloro-3- (4-fluoro- piperidin-1-yl)benzyl)-2- methyl- piperazine-1- carbonyl)-1H- pyrazol-3-yl) methane-

δ 8.03 (d, J = 2.7 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.07 (s, 1H), 6.93(d, J = 8.1 Hz, 1H), 6.86 (br, 1H), 6.30 (d, J = 2.7 Hz, 1H), 4.90- 4.94(m, 1H), 4.67-4.78 (m, 1H), 513.4 sulfonamide 4.31-4.36 (m, 1H),3.32-3.56 (m, 3H), 3.12-3.17 (m, 5H), 2.98-3.04 (m, 2H), 2.83-2.90 (m,1H), 2.62-2.66 (m, 1H), 2.05-2.25 (m, 6H), 1.49 (d, J = 6.9 Hz, 3H) 137N-(1-((2R)-4- (4-Chloro-3- (tetrahydro-1H- furo[3,4-c] pyrrol-5(3H)-yl)benzyl)-2- methyl- piperazine-1- carbonyl)-1H- pyrazol-3-yl) methane-

δ 8.05 (d, J = 2.8 Hz, 1H), 7.30 (s, 1H), 7.01 (s, 1H), 6.91-6.92 (m,1H), 6.83 (br, 1H), 6.32 (d, J = 2.8 Hz, 1H), 4.69 (br, 1H), 4.34-4.37(m, 1H), 4.00-4.04 (m, 2H), 3.68-3.71 (m, 2H), 3.54-3.57 (m, 1H), 523.5sulfonamide 3.39-3.50 (m, 1H), 3.28-3.37 (m, 3H), 3.14-3.26 (m, 5H),2.99 (br, 2H), 2.86-2.88 (m, 1H), 2.66-2.69 (m, 1H), 2.22-2.27 (m, 2H),1.47 (d, J = 6 Hz, 3H) 138 (R)-N-(1-(4- (4-Chloro-3- (4-fluoro-piperidin-1- yl)benzyl)-3- methyl- piperazine-1- carbonyl)-1H-pyrazol-3-yl) methane-

δ 8.04 (d, J = 2.7 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 6.92-7.02 (m, 3H),6.30 (d, J = 2.7 Hz, 1H), 4.75-4.94 (m, 1H), 4.15-4.18 (m, 2H),3.94-3.98 (m, 1H), 3.37-3.44 (m, 1H), 3.13-3.25 513.0 sulfonamide (m,7H), 2.98-3.04 (m, 2H), 2.72-2.75 (m, 1H), 2.59 (br, 1H), 2.01-2.25 (m,5H), 1.18 (d, J = 6.3 Hz, 3H) 139 (R)-N-(1-(4- (1-(4-Chloro-3-(4-fluoro- piperidin-1- yl)phenyl) ethyl) piperazine- 1-carbonyl)-1H-pyrazol- 3-yl)methane-

(Methanol-d₄) δ 7.97-8.09 (d, J = 2.7 Hz, 1H), 7.27- 7.39 (d, J = 8.1Hz, 1H), 7.08-7.18 (d, J = 1.8 Hz, 1H), 6.92-7.05 (d, J = 8.1 Hz, 1H),6.17-6.31 (d, J = 2.7 Hz, 1H), 4.67- 512.9 sulfonamide 4.95 (m, 1H),3.70-3.90 (br, 4H), 3.43-3.57 (m, 1H), 3.05-3.23 (m, 5H), 2.92-3.03 (m,2H), 2.58-2.72 (m, 2H), 2.41-2.58 (m, 2H), 1.89-2.20 (m, 4H), 1.33-1.48(d, J = 6.9 Hz, 3H) 140 N-(1-(5-(4- chloro-3- (Tetrahydro- 1H-furo[3,4-c]pyrrol- 5(3H)-yl) benzyl) octahydro pyrrolo[3,4-c] pyrrole-2-carbonyl)-1H- pyrazol-3-yl)

δ 8.17 (d, J = 2.8 Hz, 1H), 7.25 (s, 1H), 7.04 (br, 1H), 6.84-6.88 (m,1H), 6.36 (d, J = 2.8 Hz, 1H), 4.11 (br, 2H), 3.93- 3.96 (m, 2H),3.71-3.74 (m, 4H), 3.57 (br, 2H), 3.41 (br, 2H), 3.13 (s, 3H), 2.82-3.07(m, 535.5 methane- 6H), 2.56-2.61 (m, sulfonamide 4H) 141 N-(1-(4-(3-(4-Fluoro- piperidin-1- yl)-4- (trifluoromethyl) benzyl)-3- methyl-piperazine-1- carbonyl)-1H- pyrazol-3-yl)

δ 8.04 (s, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.33 (s, 1H), 7.18 (d, J = 8.1Hz, 1H), 6.99 (br, 1H), 6.30 (s, 1H), 4.68-5.00 (m, 1H), 4.08-4.35 (m,2H), 4.02 (m, 1H), 3.35-3.55 (m, 1H), 3.19-3.34 (m, 547.0 methane- 2H),3.14 (s, 3H), sulfonamide 3.00-3.12 (m, 2H), 2.78-2.93 (m, 2H),2.68-2.78 (m, 1H), 2.62 (m, 1H), 2.16-2.35 (m, 1H), 1.90-2.16 (m, 4H),1.08-1.27 (m, 3H) 142 (R)-N-(1-(4- (4-Chloro-3- (4-fluoro- piperidin-1-yl)benzyl)-2- methyl- piperazine-1- carbonyl)-1H- pyrazol-3-yl) methane-

δ 8.05 (d, J = 2.7 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.09 (s, 1H), 6.95(d, J = 6.6 Hz, 2H), 6.32 (d, J = 2.7 Hz, 1H), 4.76- 4.96 (m, 1H), 4.70(br, 1H), 4.34- 4.38 (m, 1H), 513.4 sulfonamide 3.35-3.59 (m, 3H),3.16-3.21 (m, 5H), 2.98-3.08 (m, 2H), 2.85-2.89 (m, 1H), 2.65-2.68 (m,1H), 2.02-2.27 (m, 6H), 1.46 (d, J = 6.6 Hz, 3H) 143 N-(1-((3S)-4-(4-Chloro-3- (tetrahydro- 1H-furo [3,4-c]pyrrol- 5(3H)-yl) benzyl)-3-methyl- piperazine-1- carbonyl)-1H- pyrazol-3-yl)

δ 8.04 (d, J = 2.7 Hz, 1H), 7.26-7.28 (m, 1H), 7.06 (br, 1H), 6.87-6.94(m, 2H), 6.30 (d, J = 2.7 Hz, 1H), 4.15 (br, 2H), 3.96- 3.99 (m, 3H),3.65-3.69 (m, 2H), 3.42 (br, 1H), 3.14-3.36 (m, 9H), 523.3 methane- 2.96(br, 2H), 2.74 sulfonamide (br, 1H), 2.61 (br, 1H), 2.23 (br, 1H), 1.19(br, 3H) 144 N-(1-(4-(3,5- Dichlorobenzyl) piperazine-1- carbonyl)-1H-pyrazol-3- yl)acetamide

δ 8.02 (d, J = 2.7 Hz, 1H), 7.68-7.73 (m, 1H), 7.38-7.40 (m, 2H), 6.88(d, J = 2.7 Hz, 1H), 3.87-4.00 (m, 4H), 3.39-3.64 (m, 2H), 2.40-2.71 (m,4H), 2.18 (s, 3H) 396.1 145 N-(1-(5-(3- Chloro-5- fluorobenzyl)octahydro- pyrrolo[3,4-c] pyrrole-2- carbonyl)-1H- pyrazol-3-yl)acetamide

δ 8.14 (d, J = 2.7 Hz, 1H), 7.71 (br, 1H), 7.10 (s, 1H), 6.91-6.99 (m,2H), 6.87 (d, J = 2.7 Hz, 1H), 4.03 (br, 2H), 3.77-3.81 (m, 2H), 3.55(s, 2H), 2.88 (br, 2H), 2.54-2.63 (m, 4H), 2.18 (s, 3H) 406.1 146N-(1-(5-(3- Chloro-5- (trifluoromethyl) benzyl)octa- hydropyrrolo[3,4-c]pyrrole- 2-carbonyl)- 1H-pyrazol-3- yl)acetamide

δ 8.14 (d, J = 2.7 Hz, 1H), 7.71 (br, 1H), 7.47- 7.53 (m, 3H), 6.88 (d,J = 2.7 Hz, 1H), 4.02 (br, 2H), 3.79-3.83 (m, 2H), 3.64 (s, 2H), 2.91(br, 2H), 2.65 (br, 2H), 2.54- 2.56 (m, 2H), 2.18 456.1 (s, 3H) 147N-(1-(4-(4- Chloro-3- (4,4-difluoro- piperidin-1- yl)benzyl) piperazine-1-carbonyl)- 1H-pyrazol-3- yl)methane- sulfonamide

(Methanol-d₄) δ 7.87-8.02 (m, 1H), 7.31-7.37 (m, 1H), 7.11-7.21 (m, 1H),6.98-7.08 (m, 1H), 6.15-6.21 (m, 1H), 3.77-3.95 (m, 4H), 3.49-3.61 (m,2H), 3.01-3.22 (m, 7H), 2.46-2.68 (m, 4H), 517.2 1.99-2.24 (m, 4H) 148(S)-N-(1-(4- (4-Chloro-3- (4-fluoro- piperidin-1- yl)benzyl)- 3-methyl-piperazine- 1-carbonyl)- 1H-pyrazol- 3-yl)methane-

δ 8.04 (d, J = 2.7 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 6.92-7.01 (m, 3H),6.30 (d, J = 2.7 Hz, 1H), 4.75-4.95 (m, 1H), 4.15-4.18 (m, 2H),3.94-3.98 (m, 1H), 3.36-3.44 (m, 1H), 3.13-3.25 535.2 [M + Na]⁺sulfonamide (m, 7H), 2.98-3.04 (m, 2H), 2.71-2.75 (m, 1H), 2.57-2.61 (m,1H), 1.99-2.24 (m, 5H), 1.15 (d, J = 6.3 Hz, 3H) 149 N-(1-(4-(3-(4-Chloro- phenoxy) benzyl) piperazine- 1-carbonyl)- 1H-pyrazol-3-yl)methane- sulfonamide

δ 8.04 (d, J = 2.7 Hz, 1H), 7.26-7.32 (m, 3H), 7.06-7.09 (m, 1H),6.95-7.01 (m, 1H), 6.87-6.94 (m, 3H), 6.31 (d, J = 2.7 Hz, 1H), 3.83(br, 4H), 3.53 (s, 2H), 3.13 (s, 490.2 3H), 2.51-2.54 (m, 4H) 150N-(1-(5-(4- Chloro-3-(2- hydroxypropan- 2-yl)benzyl) octahydropyrrolo[3,4-c] pyrrole-2- carbonyl)-1H- pyrazol-3- yl)acetamide

δ 8.13 (d, J = 2.7 Hz, 1H), 8.03 (br, 1H), 7.68 (s, 1H), 7.27-7.30 (m,1H), 7.09-7.12 (m, 1H), 6.88 (d, J = 2.7 Hz, 1H), 3.87-3.94 (m, 4H),3.58 (s, 2H), 2.86-2.92 (m, 3H), 2.59-2.62 (m, 4H), 2.19 (s, 3H), 446.21.74 (s, 6H) 151 (S)-N-(1-(4- (3-(2-Methyl- pyrrolidin- 1-yl)-4-(trifluoromethyl) benzyl) piperazine- 1-carbonyl)- 1H-pyrazol-3-yl)methane- sulfonamide

(Methanol-d₄) δ 7.96-8.09 (m, 1H), 7.26-7.61 (m, 2H), 7.05-7.16 (m, 1H),6.12-6.26 (m, 1H), 3.44-3.97 (m, 8H), 3.08-3.17 (m, 3H), 2.81-2.96 (m,1H), 2.46-2.64 (m, 4H), 2.07-2.25 (m, 1H), 1.75-2.02 (m, 2H), 515.01.48-1.65 (m, 1H), 0.94-1.05 (m, 3H) 152 N-(1-(4-(4- Chloro-3-(hexahydro- pyrrolo [3,4-c]pyrrol- 2(1H)-yl) benzyl) piperazine-1-carbonyl)- 1H-pyrazol-

(Pyridine-d₅) δ 8.40 (d, J = 2.8 Hz, 1H), 7.40-7.46 (m, 1H), 7.08 (s,1H), 6.91-6.98 (m, 1H), 6.61 (d, J = 2.8 Hz, 1H), 3.94 (br, 4H), 3.42(s, 2H), 3.34 (s, 3H), 3.10-3.18 (m, 4H), 508.2 3-yl)methane- 2.99-3.01(m, 2H), sulfonamide 2.80-2.85 (m, 2H), 2.63 (br, 2H), 2.44-2.47 (m, 4H)153 N-(1-(4-(4- Chloro-3- (5-ethyl- hexahydro- pyrrolo [3,4-c]pyrrol-2(1H)-yl) benzyl) piperazine- 1-carbonyl)- 1H-pyrazol-3- yl)methane-

(Methanol-d₄) δ 7.99 (d, J = 2.7 Hz, 1H), 7.28-7.31 (m, 1H), 7.10 (s,1H), 6.95-6.98 (m, 1H), 6.18 (d, J = 2.7 Hz, 1H), 3.85 (br, 4H), 3.53(s, 2H), 3.32-3.40 (m, 4H), 3.07 (s, 3H), 2.95-3.02 (m, 4H), 2.71-2.74(m, 2H), 546.3 sulfonamide 2.52-2.55 (m, 6H), 1.20 (t, J = 7.2 Hz, 3H)154 N-(1-(2-(6- (Trifluoro- methyl) benzo[b] thiophene-2- carbonyl)-2,8-diazaspiro[4.5] decane-8- carbonyl)-1H- pyrazol-3- yl)acetamide

δ 8.16 (s, 1H), 7.93-8.02 (m, 2H), 7.61-7.77 (m, 3H), 6.88 (br, 1H),3.94-4.03 (m, 2H), 3.62-3.83 (m, 5H), 2.19 (s, 3H), 1.98- 2.02 (m, 2H),1.74 (br, 5H) 520.2 155 N-(1-(1-(6- (Trifluoro- methyl) benzo[b]thiophene-2- carbonyl)-1,8- diazaspiro[4.5] decane-8- carbonyl)-1H-pyrazol-3- yl)acetamide

δ 8.15 (s, 1H), 7.98-8.01 (m, 2H), 7.90 (d, J = 8.4 Hz, 1H), 7.59-7.65(m, 2H), 6.87 (d, J = 2.7 Hz, 1H), 4.57-4.60 (m, 2H), 3.91 (t, J = 6.6Hz, 2H), 3.25-3.30 (m, 2H), 3.20-3.24 (m, 2H), 2.19 (s, 520.2 3H),2.10-2.15 (m, 2H), 1.93-2.02 (m, 2H), 2.47-2.50 (m, 2H) 156 (R)-N-(1-(4-(3-(2-Methyl- pyrrolidin-1- yl)-4- (trifluoromethyl) benzyl) piperazine-1-carbonyl)- 1H-pyrazol-3- yl)methane- sulfonamide

(Methanol-d₄) δ 7.93-8.21 (m, 1H), 7.28-7.71 (m, 2H), 6.98-7.21 (m, 1H),6.12-6.38 (m, 1H), 3.25-4.08 (m, 11H), 2.81-2.99 (m, 1H), 2.46-2.64 (m,4H), 1.41-2.25 (m, 4H), 0.88-1.12 (m, 3H) 515.0 157 N-(1-(4-(3-((1R,4R)- 2-Oxa-5- azabicyclo [2.2.1]heptan- 5-yl)-4- chlorobenzyl)piperazine- 1-carbonyl)- 1H-pyrazol- 3-yl)methane-

δ 8.04 (d, J = 2.7 Hz, 1H), 7.24 (s, 1H), 6.72-6.91 (m, 2H), 6.32 (d, J= 2.7 Hz, 1H), 4.61 (s, 1H), 4.43 (s, 1H), 4.09-4.12 (m, 1H), 3.74-3.90(m, 6H), 3.50 (br, 2H), 3.30-3.33 (m, 1H), 3.12 (s, 3H), 2.54 517.1 [M +Na]⁺ sulfonamide (br, 4H), 2.01-2.04 (m, 1H), 1.93-1.96 (m, 1H) 158N-(1-(4-(4- Chloro-3- ((4aS,7aR)- hexahydro- cyclopenta[b] [1,4]oxazin-4(4aH)- yl)benzyl) piperazine- 1-carbonyl)- 1H-pyrazol-3- yl)methane-

δ 8.04 (d, J = 2.7 Hz, 1H), 7.28-7.30 (m, 1H), 7.02 (s, 1H), 6.90-6.93(m, 1H), 6.32 (d, J = 2.7 Hz, 1H), 4.04 (br, 1H), 3.90-3.93 (m, 1H),3.78-3.89 (m, 6H), 3.44-3.50 (m, 3H), 3.13 (s, 3H), 2.72-2.76 (m, 1H),2.49-2.52 (m, 544.8 [M + Na]⁺ sulfonamide 4H), 1.74-1.94 (m, 4H),1.50-1.57 (m, 1H), 1.24-1.30 (m, 1H) 159 N-(1-(4-(4- Chloro-3- (8-oxa-2-azaspiro[4.5] decan-2- yl)benzyl) piperazine- 1-carbonyl)- 1H-pyrazol-3-yl)methane- sulfonamide

δ 8.04 (d, J = 2.7 Hz, 1H), 7.22 (s, 1H), 6.72-6.91 (m, 3H), 6.32 (d, J= 2.7 Hz, 1H), 3.84 (br, 3H), 3.64- 3.78 (m, 5H), 3.50 (t, J = 6.9 Hz,4H), 3.29 (s, 2H), 3.13 (s, 3H), 2.55 (br, 4H), 1.86 (t, J = 6.9 Hz,2H), 1.66-1.74 (m, 4H) 537.3 160 N-(1-(2-(3- Chloro-4- (tetrahydro-1H-furo [3,4-c]pyrrol- 5(3H)-yl) benzyl)-2,8- diazaspiro [4.5]decane-8-carbonyl)- 1H-pyrazol-3- yl)methane- sulfonamide

δ 8.00 (d, J = 2.7 Hz, 1H), 7.31 (s, 1H), 7.15-7.17 (m, 1H), 6.92 (d, J= 8.1 Hz, 1H), 6.31 (d, J = 2.7 Hz, 1H), 3.97-4.02 (m, 2H), 3.57-3.78(m, 8H), 3.23-3.28 (m, 2H), 3.13-3.18 (m, 5H), 2.89-3.01 (m, 2H), 2.67(br, 2H), 2.47 (br, 2H), 1.69-1.73 (m, 6H) 563.3 161 N-(1-(4-(2-(Pyrrolidin- 1-yl)-4- (trifluoromethyl) benzyl) piperazine- 1-carbonyl)-1H-pyrazol-3- yl)iso- butyramide

δ 8.01 (d, J = 3.0 Hz, 1H), 7.75 (br, 1H), 7.52-7.55 (m, 1H), 7.09-7.11(m, 2H), 6.90 (d, J = 3.0 Hz, 1H), 3.84 (br, 4H), 3.59 (br, 2H),3.22-3.26 (m, 4H), 2.48-2.54 (m, 5H), 1.91-1.99 (m, 4H), 1.25 (d, J =6.9 Hz, 6H) 515.4 [M + Na]⁺ 162 N-(1-(2-(2- Chlorobenzyl)-2,8-diazaspiro [4.5]decane- 8-carbonyl)- 1H-pyrazol-3- yl)methane-sulfonamide

δ 8.00-8.01 (m, 1H), 7.46-7.48 (m, 1H), 7.33-7.36 (m, 1H), 7.16-7.24 (m,2H), 6.31-6.32 (m, 1H), 3.62-3.80 (m, 6H), 3.13 (s, 3H), 2.71 (t, J =6.8 Hz, 2H), 2.52 (s, 2H), 1.65-1.74 (m, 6H) 452.2 163 N-(1-(2-(3-Chlorobenzyl)- 2,8-diazaspiro [4.5]decane-8- carbonyl)-1H- pyrazol-3-yl)methane- sulfonamide

δ 8.00-8.01 (m, 1H), 7.34 (s, 1H), 7.24 (br, 3H), 6.31-6.32 (m, 1H),3.61-3.79 (m, 6H), 3.13 (s, 3H), 2.64 (br, 2H), 2.45 (br, 2H), 1.69 (br,6H) 452.1 164 N-(1-(2-(4- Chlorobenzyl)- 2,8-diazaspiro [4.5]decane-8-carbonyl)- 1H-pyrazol-3- yl)methane- sulfonamide

δ 8.00-8.01 (m, 1H), 7.29 (br, 4H), 6.30-6.32 (m, 1H), 3.61-3.78 (m,6H), 3.18 (s, 3H), 2.64 (br, 2H), 2.43 (br, 2H), 1.69 (br, 6H) 452.0 165N-(1-(2- Benzyl-2,8- diazaspiro [4.5]decane- 8-carbonyl)- 1H-pyrazol-3-yl)methane- sulfonamide

δ 7.99-8.00 (m, 1H), 7.26-7.35 (m, 5H), 6.30-6.31 (m, 1H), 3.61-3.78 (m,6H), 3.12 (s, 3H), 2.69 (t, J = 6.4 Hz, 2H), 2.48 (br, 2H), 1.64- 1.75(m, 6H) 418.1 166 N-(1-(5-(3- Morpholino- 5-(trifluoro- methyl)benzyl)octahydro- pyrrolo[3,4-c] pyrrole-2- carbonyl)-1H- pyrazol-3-yl)acetamide

δ 8.15 (d, J = 2.8 Hz, 1H), 7.75 (br, 1H), 7.02-7.10 (m, 3H), 6.60 (d, J= 2.8 Hz, 1H), 4.02 (br, 2H), 3.87- 3.93 (m, 6H), 3.63 (br, 2H),3.30-3.33 (m, 4H), 2.92 (br, 2H), 2.60 (br, 4H), 507.2 2.21 (s, 3H) 167N-(1-(5-(3- Chloro-5- morpholino- benzyl) octahydro- pyrrolo [3,4-c]pyrrole-2- carbonyl)-1H- pyrazol-3- yl)acetamide

δ 8.15 (d, J = 2.8 Hz, 1H), 7.79-7.82 (m, 1H), 6.90 (d, J = 2.8 Hz, 1H),6.77-6.82 (m, 3H), 4.03 (br, 2H), 3.84-3.90 (m, 6H), 3.53 (s, 2H), 3.15-3.18 (m, 4H), 3.89 (br, 2H), 2.63 (br, 2H), 2.54- 473.3 2.56 (m, 2H),2.20 (s, 3H) 168 N-(1-(5-(3- (Pyrrolidin- 1-yl)-5- (trifluoromethyl)benzyl)octa- hydropyrrolo [3,4-c]pyrrole- 2-carbonyl)- 1H-pyrazol-3-yl)acetamide

δ 8.15 (d, J = 2.8 Hz, 1H), 7.78 (br, 1H), 6.90 (d, J = 2.8 Hz, 1H),6.83 (s, 1H), 6.64-6.70 (m, 2H), 4.02 (br, 2H), 3.86 (br, 2H), 3.60 (br,2H), 3.30 (t, J = 6.4 Hz, 4H), 2.91 (br, 2H), 2.66 (br, 2H), 491.32.57-2.59 (m, 2H), 2.20 (s, 3H), 1.99- 2.06 (m, 4H) 169 N-(1-(5-(2-Chloro-4- (pyrrolidin-1- yl)benzyl) octahydro pyrrolo[3,4-c] pyrrole-2-carbonyl)-1H- pyrazol-3- yl)acetamide

δ 8.14 (d, J = 2.8 Hz, 1H), 7.90-7.94 (m, 1H), 7.20-7.23 (m, 1H), 6.89(d, J = 2.8 Hz, 1H), 6.54 (s, 1H), 6.41- 6.45 (m, 1H), 4.04 (br, 2H),3.70- 3.79 (m, 4H), 3.27 (t, J = 6.4 Hz, 4H), 2.89 (br, 2H), 2.75 457.1(br, 2H), 2.59-2.61 (m, 2H), 2.20 (s, 3H), 1.99-2.05 (m, 4H) 170N-(1-(5-(4- Chlorobenzyl) octahydro- pyrrolo[3,4-c] pyrrole-2-carbonyl)-1H- pyrazol-3- yl)acetamide

δ 8.13 (s, 1H), 7.77 (br, 1H), 7.21-7.36 (m, 3H), 6.87 (s, 1H), 4.02(br, 2H), 3.78 (br, 2H), 3.58 (s, 2H), 2.88 (br, 2H), 2.64 (br, 2H),2.46-2.58 (m, 2H), 2.18 (s, 3H) 388.1 171 N-(1-(5-(4- Morpholino-3-(trifluoromethyl) benzyl)octa- hydropyrrolo [3,4-c]pyrrole- 2-carbonyl)-1H-pyrazol-3- yl)acetamide

δ 8.16 (d, J = 2.8 Hz, 1H), 7.73 (br, 1H), 7.58 (s, 1H), 7.49-7.51 (m,1H), 7.31-7.40 (m, 1H), 6.90 (d, J = 2.8 Hz, 1H), 4.05 (br, 2H),3.84-3.86 (m, 6H), 3.62 (s, 2H), 2.92-2.94 (m, 6H), 507.2 2.65 (br, 2H),2.54-2.56 (m, 2H), 2.21 (s, 3H) 172 N-(1-(5-(3- Chloro-5- (pyrrolidin-1-yl)benzyl) octahydro pyrrolo[3,4-c] pyrrole-2- carbonyl)-1H-pyrazol-3- yl)acetamide

δ 8.13 (d, J = 2.7 Hz, 1H), 7.80 (br, 1H), 6.87 (d, J = 2.7 Hz, 1H),6.57 (s, 1H), 6.42 (s, 2H), 3.70-4.12 (m, 4H), 3.55 (br, 2H), 3.17-3.31(m, 4H), 2.91 (br, 2H), 2.46-2.82 (m, 4H), 2.19 (s, 3H), 1.93- 457.22.04 (m, 4H) 173 N-(1-(5-(3- Phenoxy- benzyl)octa- hydropyrrolo[3,4-c]pyrrole- 2-carbonyl)- 1H-pyrazol-3- yl)acetamide

δ 8.12 (s, 1H), 7.80 (br, 1H), 7.28-7.39 (m, 3H), 7.04-7.14 (m, 2H),6.96-7.04 (m, 3H), 6.84-6.95 (m, 2H), 4.02 (br, 2H), 3.49-3.88 (m, 4H),2.45-3.02 (m, 6H), 2.18 (s, 3H) 446.2 174 N-(1-(5-(2,4- Dichloro-benzyl)octa- hydropyrrolo [3,4-c]pyrrole- 2-carbonyl)- 1H-pyrazol-3-yl)acetamide

δ 8.13 (s, 1H), 7.97 (br, 1H), 7.32-7.45 (m, 2H), 7.16-7.26 (m, 1H),6.88 (s, 1H), 4.05 (br, 2H), 3.60- 3.89 (m, 4H), 2.89 (br, 2H), 2.52-2.79 (m, 4H), 2.18 (s, 3H) 422.0 175 N-(1-(2-(3- (Trifluoro- methyl)benzyl)-2,8- diazaspiro [4.5]decane- 8-carbonyl)- 1H-pyrazol-3-

δ 7.97 (d, J = 2.7 Hz, 1H), 7.79 (br, 1H), 7.59 (s, 1H), 7.53-7.50 (m,2H), 7.45-7.40 (m, 1H), 6.86 (d, J = 2.7 Hz, 1H), 3.80-3.60 (m, 6H),2.65 (t, 450.2 yl)acetamide J = 6.6 Hz, 2H), 2.44 (br, 2H), 2.18 (s,3H), 1.75-1.63 (m, 6H) 176 N-(1-(2-(3- Chloro-5- fluorobenzyl)-2,8-diazaspiro [4.5]decane- 8-carbonyl)- 1H-pyrazol-3- yl)acetamide

δ 7.98 (d, J = 2.7 Hz, 1H), 7.72 (br, 1H), 7.14 (br, 1H), 7.00-6.98 (m,2H), 6.87 (d, J = 2.7 Hz, 1H), 3.81-3.77 (m, 2H), 3.68-3.60 (m, 2H),2.44 (br, 2H), 2.65 (br, 2H), 2.45 (br, 2H), 2.18 (s, 3H), 1.70 (s, 6H)434.2 177 N-(1-(4-((4- Chloro-3- (tetrahydro- 1H-furo [3,4-c]pyrrol-5(3H)-yl) benzyl)(methyl) amino) piperidine- 1-carbonyl)-

δ 8.04 (d, J = 2.8 Hz, 1H), 7.29-7.27 (m, 1H), 6.98 (s, 1H), 6.91-6.88(m, 1H), 6.34 (d, J = 2.8 Hz, 1H), 4.60- 4.57 (m, 2H), 4.02-4.00 (m,2H), 3.71-3.68 (m, 2H), 3.56 (s, 2H), 3.34- 537.3 1H-pyrazol-3- 3.30 (m,2H), yl)methane- 3.19-3.16 (m, 5H), sulfonamide 3.04-2.98 (m, 4H),2.76-2.70 (m, 1H), 2.23 (s, 3H), 1.93- 1.90 (m, 2H), 1.76-1.66 (m, 2H)178 N-(1-((2S)-2- Methyl-4-(3- (tetrahydro- 1H-furo [3,4-c]pyrrol-5(3H)-yl)-4- (trifluoromethyl) benzyl) piperazine- 1-carbonyl)-1H-pyrazol-3-

δ 8.03 (d, J = 2.8 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.09(d, J = 8.0 Hz, 1H), 6.29 (d, J = 2.8 Hz, 1H), 4.69 (br, 1H), 4.38- 4.34(m, 1H), 4.06-4.02 (m, 2H), 3.61-3.57 (m, 3H), 557.2 yl)methane-3.48-3.39 (m, 2H), sulfonamide 3.20-3.16 (m, 2H), 3.14 (s, 3H), 3.04-2.99 (m, 2H), 2.93-2.90 (m, 2H), 2.87-2.84 (m, 1H), 2.66-2.63 (m, 1H),2.28-2.21 (m, 2H), 1.45 (d, J = 6.8 Hz, 3H) 179 N-(1-((3S)-3-Methyl-4-(3- (tetrahydro- 1H-furo [3,4-c]pyrrol- 5(3H)-yl)-4-(trifluoromethyl) benzyl) piperazine- 1-carbonyl)- 1H-pyrazol-3-

δ 8.04 (d, J = 2.8 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.24 (br, 1H),7.09 (d, J = 8.0 Hz, 1H), 6.30 (d, J = 2.8 Hz, 1H), 4.17 (br, 2H), 4.04-4.00 (m, 3H), 3.61- 3.58 (m, 2H), 3.44 (br, 1H), 3.31- 557.1 yl)methane-3.17 (m, 4H), 3.13 sulfonamide (s, 3H), 3.03-3.01 (m, 2H), 2.95-2.91 (m,2H), 2.76-2.74 (m, 1H), 2.63 (br, 1H), 2.26 (br, 1H), 1.18 (br, 3H) 180N-(1-((2R)-2- Methyl-4-(3- (tetrahydro- 1H-furo [3,4-c]pyrrol-5(3H)-yl)-4- (trifluoromethyl) benzyl) piperazine- 1-carbonyl)-1H-pyrazol-3-

δ 8.03 (d, J = 2.8 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.29 (s, 1H),7.20- 6.90 (m, 2H), 6.29 (d, J = 2.8 Hz, 1H), 4.70 (br, 1H), 4.39-4.36(m, 1H), 4.06-4.02 (m, 2H), 3.65-3.57 (m, 3H), 3.50-3.42 (m, 2H), 557.1yl)methane- 3.20-3.14 (m, 5H), sulfonamide 3.04-2.99 (m, 2H), 2.93-2.88(m, 3H), 2.70-2.66 (m, 1H), 2.32-2.20 (m, 2H), 1.45 (d, J = 6.8 Hz, 3H)181 N-(1-(4-(3- (Tetrahydro- 1H-furo [3,4-c]pyrrol- 5(3H)-yl)-4-(trifluoromethyl) benzyl) piperazine- 1-carbonyl)- 1H-pyrazol-3-yl)methane-

δ 8.04 (d, J = 2.8 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.24 (s, 1H), 7.08(d, J = 8.0 Hz, 1H), 6.30 (d, J = 2.8 Hz, 1H), 4.04- 4.00 (m, 2H), 3.86(br, 4H), 3.62- 3.57 (m, 4H), 3.21-3.15 (m, 2H), 543.2 sulfonamide 3.13(s, 3H), 3.03- 3.00 (m, 2H), 2.93 (br, 2H), 2.56 (br, 4H) 182N-(1-((3R)-3- Methyl-4-(3- (tetrahydro- 1H-furo [3,4-c]pyrrol-5(3H)-yl)-4- (trifluoromethyl) benzyl) piperazine- 1-carbonyl)-1H-pyrazol-3-

δ 8.04 (d, J = 2.8 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.10-7.04 (m, 2H),6.30 (d, J = 2.8 Hz, 1H), 4.18 (br, 2H), 4.06-4.00 (m, 3H), 3.61-3.58(m, 2H), 3.48 (br, 1H), 3.35-3.19 (m, 4H), 3.13 (s, 3H), 3.04- 557.3yl)methane- 3.02 (m, 2H), sulfonamide 2.97-2.91 (m, 2H), 2.78-2.68 (m,2H), 2.29 (br, 1H), 1.21 (br, 3H) 183 N-(1-(4-((4- Chloro-3-(pyrrolidin- 1-yl)benzyl) (methyl)amino)- 4-methyl- piperidine-1-carbonyl)- 1H-pyrazol-3- yl)methane- sulfonamide

δ 8.05 (d, J = 2.8 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 6.88 (s, 1H), 6.80(d, J = 8.4 Hz, 1H), 6.34 (d, J = 2.8 Hz, 1H), 4.04- 4.01 (m, 2H), 3.78-3.72 (m, 2H), 3.51 (s, 2H), 3.46-3.32 (m, 4H), 3.15 (s, 509.2 3H), 2.12(s, 3H), 2.04-2.01 (m, 2H), 1.98-1.95 (m, 4H), 1.63-1.58 (m, 2H), 1.06(s, 3H) 184 N-(1-(4-(((5- Chloro-2- (trifluoromethyl) benzyl)(methyl)amino)methyl) piperidine- 1-carbonyl)- 1H-pyrazol-3- yl)methane-sulfonamide

δ 8.01 (d, J = 2.7 Hz, 1H), 7.81 (s, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.31(d, J = 8.1 Hz, 1H), 6.87 (br, 1H), 6.32 (d, J = 2.7 Hz, 1H), 4.51- 4.47(m, 2H), 3.61 (s, 2H), 3.14 (s, 3H), 3.05¬-2.96 508.0 (m, 2H), 2.30-2.28(m, 2H), 2.22 (s, 3H), 1.94-1.89 (m, 2H), 1.82 (br, 1H), 1.32-1.20 (m,2H) 185 (S)-N-(1-(3- Methyl-4-(4- (trifluoromethyl)- 3-(4-(trifluoro-methyl) piperidin-1- yl)benzyl) piperazine- 1-carbonyl)- 1H-pyrazol-3-

(Methanol-d4) δ 8.02 (d, J = 2.9 Hz, 1H), 7.62-7.55 (m, 1H), 7.52-7.41(br, 1H), 7.34-7.23 (m, 1H), 6.20 (d, J = 2.9 Hz, 1H), 4.34-4.20 (m,1H), 4.20-4.10 (m, 1H), 4.10-4.00 (m, 1H), 597.1 yl)methane- 3.54-3.39(m, 1H), sulfonamide 3.39-3.31 (m, 1H), 3.30-3.18 (m, 1H), 3.15-3.03 (m,5H), 2.89-2.70 (m, 3H), 2.70-2.57 (m, 1H), 2.38-2.21 (m, 2H), 2.00-1.84(m, 2H), 1.80-1.62 (m, 2H), 1.22-1.12 (m, 3H) 186 (S)-N-(1-(4-(4-Chloro-3- (4,4-difluoro- piperidin-1- yl)benzyl)- 3-methyl-piperazine- 1-carbonyl)- 1H-pyrazol-3- yl)methane-

(Methanol-d4) δ 8.02 (d, J = 2.9 Hz, 1H), 7.39-7.28 (m, 1H), 7.19-7.12(m, 1H), 7.10-7.00 (m, 1H), 6.20 (d, J = 2.9 Hz, 1H), 4.36-4.06 (m, 2H),4.05-3.94 (m, 1H), 3.48-3.37 (m, 1H), 531.1 sulfonamide 3.29-3.18 (m,2H), 3.18-3.04 (m, 7H), 2.85-2.73 (m, 1H), 2.68-2.52 (m, 1H), 2.32-2.01(m, 5H), 1.19 (d, J = 6.2 Hz, 3H) 187 (S)-N-(1-(4- (3-(4-Fluoro-piperidin- 1-yl)-4- (trifluoromethyl) benzyl)-3- methyl- piperazine-1-carbonyl)- 1H-pyrazol-3-

(Methanol-d4) δ 8.04 (d, J = 2.9 Hz, 1H), 7.63-7.53 (m, 1H), 7.51-7.43(br, 1H), 7.33-7.24 (m, 1H), 6.22 (d, J = 2.8 Hz, 1H), 4.85-4.65 (m,1H), 4.40-3.97 (m, 3H), 3.52-3.40 (m, 1H), 547.1 yl)methane- 3.40-3.33(m, 1H), sulfonamide 3.29-3.19 (m, 1H), 3.13 (s, 3H), 3.12- 3.00 (m,2H), 2.92-2.71 (m, 3H), 2.71-2.58 (m, 1H), 2.38-2.22 (m, 1H), 2.55-1.80(m, 4H), 1.19 (d, J = 6.3 Hz, 3H) 188 (S)-N-(1-(4- (4-Chloro-3-(4-(trifluoro- methyl) piperidin-1- yl)benzyl)- 3-methyl- piperazine-1-carbonyl)- 1H-pyrazol-3-

(Methanol-d4) δ 8.04 (d, J = 2.8 Hz, 1H), 7.39-7.28 (m, 1H), 7.09-7.20(m, 1H), 7.08-6.95 (m, 1H), 6.22 (d, J = 2.9 Hz, 1H), 4.37-4.08 (m, 2H),4.08-3.96 (m, 1H), 3.55-3.36 (m, 3H), 563.1 yl)methane- 3.30-3.19 (m,2H), sulfonamide 3.13 (s, 3H), 2.87- 2.58 (m, 4H), 2.40-2.23 (m, 2H),2.08-1.89 (m, 2H), 1.89-1.68 (m, 2H), 1.20 (d, J = 2.9 Hz, 3H) 189N-(1-((S)-4- (4-Chloro-3- ((S)-3-fluoro- pyrrolidin- 1-yl)benzyl)-3-methyl- piperazine- 1-carbonyl)- 1H-pyrazol-3- yl)methane- sulfonamide

(Methanol-d4) δ 8.03 (d, J = 2.8 Hz, 1H), 7.29-7.18 (m, 1H), 7.04-6.95(m, 1H), 6.88-6.77 (m, 1H), 6.21 (d, J = 2.9 Hz, 1H), 5.44-5.15 (m, 1H),4.31-4.08 (m, 2H), 4.03-3.96 (m, 1H), 3.96-3.76 (m, 1H), 3.72-3.58 (m,1H), 499.1 3.51-3.34 (m, 2H), 3.29-3.15 (m, 3H), 3.12 (s, 3H), 2.85-2.75 (m, 1H), 2.70-2.53 (m, 1H), 2.32-2.20 (m, 2H), 2.20-2.03 (m, 1H),1.19 (d, J = 6.3 Hz, 1H) 190 (S)-N-(1-(4- (4-Chloro-3- (4-isopropyl-3-oxo- piperazin-1- yl)benzyl)- 3-methyl- piperazine- 1-carbonyl)-1H-pyrazol-3- yl)methane-

(Methanol-d4) δ 8.02 (d, J = 2.8 Hz, 1H), 7.38-7.31 (m, 1H), 7.11-7.18(m, 1H), 7.11-7.03 (m, 1H), 6.20 (d, J = 2.9 Hz, 1H), 4.84-4.76 (m, 1H),4.31-4.07 (m, 2H), 4.07-3.95 (m, 1H), 3.74 (s, 2H), 3.49- 552.2sulfonamide 3.34 (m, 5H), 3.30-3.18 (m, 2H), 3.11 (s, 3H), 2.84- 2.71(m, 1H), 2.69-2.53 (m, 1H), 2.32-2.19 (m, 1H), 1.24-1.13 (m, 9H) 1911-(3-((5-(3- Acetamido- 1H-pyrazole- 1-carbonyl) hexahydro pyrrolo[3,4-c]pyrrol- 2(1H)-yl) methyl)-5- (trifluoromethyl) phenyl)cyclo-pentane-1-

(Methanol-d4) δ 8.12 (d, J = 2.7 Hz, 1H), 7.68 (s, 1H), 7.57 (s, 1H),7.48 (s, 1H), 6.80 (d, J = 2.7 Hz, 1H), 3.94 (br, 4H), 3.78 (s, 2H),2.95 (br, 2H), 2.86-2.78 (m, 2H), 2.68-2.62 (m, 4H), 2.11 (s, 3H), 1.86-534.2 carboxylic acid 1.72 (m, 6H) 192 N-(1-((S)-4- (3-((S)-3- Fluoro-pyrrolidin- 1-yl)-4- (trifluoromethyl) benzyl)-3- methyl- piperazine-1-carbonyl)-1H- pyrazol-3-yl) methane-

(Methanol-d4) δ 8.04 (d, J = 2.8 Hz, 1H), 7.59- 7.48 (m, 1H), 7.23- 7.12(br, 1H), 7.04-6.95 (m, 1H), 6.22 (d, J = 2.9 Hz, 1H), 5.47-5.15 (m,1H), 4.35-4.09 (m, 2H), 4.09-3.98 (m, 1H), 3.83-3.53 (m, 2H), 3.50-3.32533.3 sulfonamide (m, 3H), 3.29-3.18 (m, 2H), 3.12 (s, 3H), 2.85-2.74(m, 1H), 2.69-2.59 (m, 1H), 2.35-2.05 (m, 3H), 1.19 (d, J = 6.3 Hz, 3H)193 1-(3-(((1-(3- Acetamido- 1H-pyrazole- 1-carbonyl) piperidin-4-yl)(methyl) amino)methyl)- 5-(trifluoro- methyl)phenyl) cyclopentane-1-carboxylic acid

(Methanol-d4) δ 8.05 (d, J = 2.7 Hz, 1H), 7.71 (s, 1H), 7.63 (s, 1H),7.58 (s, 1H), 6.81 (d, J = 2.7 Hz, 1H), 4.68-4.64 (m, 2H), 3.92 (s, 2H),3.10- 2.97 (m, 3H), 2.73- 2.70 (m, 2H), 2.41 (s, 3H), 2.15 (s, 3H),2.05-2.01 (m, 536.3 2H), 1.98-1.75 (m, 8H) 194 N-(1-((2S,4S)- 4-((4-chloro-3- (Tetrahydro- 1H-furo [3,4-c]pyrrol- 5(3H)-yl) benzyl)(methyl)amino)-2- methyl-

(Methanol-d4) δ 8.04 (d, J = 2.8 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.09(s, 1H), 6.96- 6.94 (m, 1H), 6.24 (d, J = 2.8 Hz, 1H), 4.25-4.20 (m,2H), 4.03-3.99 (m, 2H), 3.64-3.60 (m, 551.2 piperidine-1- 4H), 3.47-3.40(m, carbonyl)- 1H), 3.19-3.16 (m, 1H-pyrazol-3- 4H), 3.14 (s, 3H),yl)methane- 2.99-2.95 (m, 2H), sulfonamide 2.78-2.76 (m, 1H), 2.30-2.24(m, 4H), 2.07-2.04 (m, 1H), 1.78-1.71 (m, 2H), 1.43 (d, J = 6.4 Hz, 3H)195 N-(1-(1-(4- Chloro-3- (pyrrolidin-1- yl)benzyl)- 1,8-diazaspiro[4.5]decane- 8-carbonyl)- 1H-pyrazol- 3-yl)methane- sulfonamide

(Methanol-d4) δ 8.05 (d, J = 2.8 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.98(d, J = 2.0 Hz, 1H), 6.86-6.79 (m, 1H), 6.25 (d, J = 2.8 Hz, 1H),4.70-4.51 (m, 2H), 3.63 (s, 2H), 3.39- 3.34 (m, 4H), 521.2 3.21-3.08 (m,5H), 2.82-2.72 (m, 2H), 2.03-1.90 (m, 8H), 1.90-1.79 (m, 2H), 1.61-1.50(m, 2H) 196 N-(1-(4-((4- Chloro-2- (4-fluoro- piperidin-1- yl)benzyl)(methyl)amino)- 4-methyl- piperidine- 1-carbonyl)- 1H-pyrazol-3-yl)methane- sulfonamide

(Methanol-d4) δ 8.05 (d, J = 2.8 Hz, 1H), 7.70-7.60 (m, 1H), 7.18-7.05(m, 2H), 6.25 (d, J = 2.8 Hz, 1H), 4.90-4.68 (m, 1H), 4.00-3.88 (m, 2H),3.88-3.75 (m, 2H), 3.68 (s, 2H), 3.14 (s, 3H), 3.08-2.97 (m, 2H),2.88-2.75 (m, 2H), 2.15 (s, 3H), 2.10-2.00 (m, 4H), 2.00-1.90 (m, 2H),1.72-1.60 (m, 2H), 1.16 (s, 3H) 541.3 197 N-(1-(4-((4- Chloro-2-(tetrahydro- 1H-furo [3,4-c]pyrrol- 5(3H)-yl) benzyl)(methyl) amino)-4-methyl- piperidine- 1-carbonyl)- 1H-pyrazol-3- yl)methane- sulfonamide

(Methanol-d4) δ 8.05 (d, J = 2.8 Hz, 1H), 7.70-7.60 (m, 1H), 7.12-7.00(m, 2H), 6.25 (d, J = 2.8 Hz, 1H), 4.10-4.00 (m, 2H), 4.00-3.88 (m, 2H),3.88-3.72 (m, 2H), 3.72-3.58 (m, 4H), 3.13 (s, 3H), 3.12- 3.02 (m, 2H),3.02- 2.87 (m, 4H), 2.13 (s, 3H), 2.10-1.98 (m, 2H), 1.74-1.57 (m, 2H),1.15 (s, 3H) 551.2 198 N-(1-(4-((4- Chloro-2- morpholino- benzyl)(methyl)amino)- 4-methyl- piperidine- 1-carbonyl)- 1H-pyrazol-3-yl)methane- sulfonamide

(Methanol-d4) δ 8.05 (d, J = 2.8 Hz, 1H), 7.70-7.60 (m, 1H), 7.18-7.08(m, 2H), 6.25 (d, J = 2.8 Hz, 1H), 4.05-3.88 (m, 2H), 3.88-3.73 (m, 6H),3.69 (s, 2H), 3.14 (s, 3H), 2.95-2.80 (m, 4H), 2.14 (s, 3H), 2.10-2.00(m, 2H), 1.73-1.59 (m, 2H), 1.16 (s, 3H) 525.2 199 N-(1-((S)-4-(4-Chloro-3- ((R)-2- methyl- pyrrolidin- 1-yl)benzyl)- 3-methyl-piperazine- 1-carbonyl)- 1H-pyrazol-3- yl)methane-

δ 8.05 (d, J = 2.8 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.06-6.86 (m, 2H),6.80 (d, J = 8.0 Hz, 1H), 6.32 (d, J = 2.8 Hz, 1H), 4.28-4.09 (m, 2H),4.08-3.94 (m, 2H), 3.93-3.83 (m, 1H), 3.47-3.34 (m, 1H), 495.3sulfonamide 3.28-3.10 (m, 5H), 3.06-2.92 (m, 1H), 2.85-2.72 (m, 1H),2.68-2.53 (m, 1H), 2.29-2.16 (m, 2H), 2.04-1.91 (m, 1H), 1.89-1.72 (m,1H), 1.70-1.56 (m, 1H), 1.19 (d, J = 6.1 Hz, 3H), 1.06 (d, J = 6.0 Hz,3H) 200 N-(1-((R)- 4-(4-Chloro- 3-((R)-2- methyl- pyrrolidin-1-yl)benzyl)- 3-methyl- piperazine- 1-carbonyl)- 1H-pyrazol-3-yl)methane-

δ 8.05 (d, J = 2.8 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 6.90 (s, 1H), 6.81(d, J = 8.0 Hz, 1H), 6.32 (d, J = 2.8 Hz, 1H), 4.25-4.05 (m, 2H),4.03-3.91 (m, 2H), 3.90-3.82 (m, 1H), 3.54-3.37 (m, 1H), 495.3sulfonamide 3.33-3.18 (m, 2H), 3.15 (s, 3H), 3.05- 2.93 (m, 1H),2.84-2.73 (m, 1H), 2.68-2.55 (m, 1H), 2.33-2.14 (m, 2H), 2.03-1.91 (m,1H), 1.89-1.74 (m, 1H), 1.69-1.54 (m, 1H), 1.19 (d, J = 6.1 Hz, 3H),1.06 (d, J = 6.0 Hz, 3H) 201 (R)-N-(1-(4- (4-Chloro-3- (4,4-difluoro-piperidin-1- yl)benzyl)-3- methyl- piperazine- 1-carbonyl)-1H-pyrazol-3- yl)methane-

(Methanol-d4) δ 8.15-8.02 (m, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.17 (s,1H), 7.05 (d, J = 8.1 Hz, 1H), 6.29-6.20 (m, 1H), 4.40-4.09 (m, 2H),4.03 (d, J = 13.3 Hz, 1H), 3.52-3.37 531.2 sulfonamide (m, 1H),3.30-3.20 (m, 2H), 3.20-3.05 (m, 7H), 2.83-2.75 (m, 1H), 2.68-2.58 (m,1H), 2.27 (t, J = 11.5 Hz, 1H), 2.20-2.09 (m, 4H), 1.21 (d, J = 6.0 Hz,3H) 202 (R)-N-(1-(4- (4-Chloro-3- (4-(trifluoro- methyl) piperidin-1-yl)benzyl)- 3-methyl- piperazine- 1-carbonyl)- 1H-pyrazol-3-

δ 8.06 (d, J = 2.8 Hz, 1H), 7.35-7.30 (m, 1H), 7.03-6.94 (m, 2H), 6.32(d, J = 2.8 Hz, 1H), 4.26-4.06 (m, 2H), 4.05-3.93 (m, 1H), 3.55-3.35 (m,3H), 3.31-3.17 (m, 2H), 3.16 (s, 3H), 2.81- 563.3 yl)methane- 2.55 (m,4H), sulfonamide 2.31-2.10 (m, 2H), 2.04-1.95 (m, 2H), 1.94-1.79 (m,2H), 1.19 (d, J = 6.2 Hz, 3H) 203 N-(1-((R)-4- (4-Chloro-3- ((S)-3-fluoro- pyrrolidin-1- yl)benzyl)-3- methyl- piperazine- 1-carbonyl)-1H-pyrazol-3- yl)methane- sulfonamide

δ 8.06 (d, J = 2.8 Hz, 1H), 7.28-7.24 (m, 1H), 6.89 (s, 1H), 6.84-6.79(m, 1H), 6.32 (d, J = 2.8 Hz, 1H), 5.44- 5.25 (m, 1H), 4.28-4.10 (m,2H), 4.08-3.91 (m, 2H), 3.71-3.61 (m, 1H), 3.58-3.40 (m, 2H), 3.39-3.30(m, 1H), 499.2 3.29-3.19 (m, 2H), 3.15 (s, 3H), 2.82- 2.73 (m, 1H),2.69-2.55 (m, 1H), 2.40-2.05 (m, 3H), 1.19 (d, J = 5.6 Hz, 3H) 204N-(1-(1-(4- Chloro-2- (4-fluoro- piperidin- 1-yl)benzyl)- 1,8-diazaspiro[4.5]decane- 8-carbonyl)- 1H-pyrazol-3- yl)methane- sulfonamide

(Methanol-d4) δ 8.06 (d, J = 2.8 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.13(d, J = 2.0 Hz, 1H), 7.09-7.02 (m, 1H), 6.25 (d, J = 2.8 Hz, 1H),4.90-4.70 (m, 1H), 4.69-4.55 (m, 2H), 3.75 (s, 2H), 3.21- 3.10 (m, 5H),3.09-3.00 (m, 2H), 2.88-2.75 (m, 4H), 2.14-1.90 (m, 8H), 1.90-1.78 (m,2H), 1.61-1.51 (m, 2H) 553.2 205 N-(1-(1-(4- Chloro-2- (tetrahydro-1H-furo [3,4-c]pyrrol- 5(3H)-yl) benzyl)-1,8- diazaspiro [4.5]decane-8-carbonyl)- 1H-pyrazol-3- yl)methane- sulfonamide

(Methanol-d4) δ 8.06 (d, J = 2.8 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.10(d, J = 2.0 Hz, 1H), 7.08-7.00 (m, 1H), 6.26 (d, J = 2.8 Hz, 1H),4.70-4.55 (m, 2H), 4.02-3.91 (m, 2H), 3.76 (s, 2H), 3.71- 3.61 (m, 2H),3.21-3.05 (m, 7H), 3.01-2.89 (m, 4H), 2.81-2.71 (m, 2H), 2.03-1.90 (m,4H), 1.90-1.79 (m, 2H), 563.3 1.62-1.50 (m, 2H) 206 N-(1-(4-((4-Chloro-3- (4-fluoro- piperidin-1- yl)benzyl) (methyl)amino) piperidine-1-carbonyl)- 1H-pyrazol-3- yl)methane-

(Methanol-d4) δ 8.04 (d, J = 2.5 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.16(s, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.24 (d, J = 2.6 Hz, 1H), 4.90-4.70(m, 1H), 4.70-4.47 (m, 2H), 527.3 sulfonamide 3.63 (s, 2H), 3.25- 3.10(m, 5H), 3.10-2.90 (m, 4H), 2.84-2.74 (m, 1H), 2.26 (s, 3H), 2.17- 1.90(m, 6H), 1.80-1.68 (m, 2H) 207 (S)-N-(1-(2- Methyl-4- ((3-methyl- [1,1′-biphenyl]- 4-yl)methyl) piperazine- 1-carbonyl)- 1H-pyrazol-3-yl)acetamide

δ 8.03 (d, J = 2.8 Hz, 1H), 7.74 (br, 1H), 7.63-7.61 (m, 2H), 7.48-7.44(m, 3H), 7.41-7.28 (m, 3H), 6.89 (d, J = 2.8 Hz, 1H), 4.75 (br, 1H),4.36- 4.32 (m, 1H), 3.55-3.47 (m, 2H), 3.43-3.37 (m, 1H), 432.32.88-2.85 (m, 1H), 2.75-2.72 (m, 1H), 2.48 (s, 3H), 2.39- 2.32 (m, 1H),2.23-2.13 (m, 4H), 1.44 (d, J = 6.8 Hz, 3H) 208 (R)-N-(1-(2- Methyl-4-((3-methyl- [1,1′- biphenyl]- 4-yl)methyl) piperazine- 1-carbonyl)-1H-pyrazol-3- yl)acetamide

δ 8.03 (d, J = 2.4 Hz, 1H), 7.78 (br, 1H), 7.63-7.61 (m, 2H), 7.48-7.41(m, 3H), 7.39-7.28 (m, 3H), 6.89 (d, J = 2.4 Hz, 1H), 4.75 (br, 1H),4.35- 4.32 (m, 1H), 3.54-3.50 (m, 2H), 3.47-3.36 (m, 1H), 432.22.87-2.85 (m, 1H), 2.75-2.72 (m, 1H), 2.48 (s, 3H), 2.39- 2.32 (m, 1H),2.23-2.18 (m, 4H), 1.44 (d, J = 6.8 Hz, 3H) 209 N-(1-(4-((4- Chloro-3-(4-fluoro- piperidin- 1-yl)benzyl) oxy) piperidine- 1-carbonyl)-1H-pyrazol-3- yl)methane-

(Methanol-d4) δ 8.04 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.17(s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.25 (d, J = 2.4 Hz, 1H), 4.75-4.74(m, 1H), 4.58-4.53 (m, 2H), 514.1 sulfonamide 4.08 (br, 2H), 3.79-3.75(m, 1H), 3.62-3.58 (m, 2H), 3.20-3.15 (m, 5H), 3.01-2.96 (m, 2H),2.15-1.98 (m, 6H), 1.80-1.72 (m, 2H) 210 N-(1-((3S,4S)- 3-Fluoro-4-(3-(4-fluoro- piperidin-1- yl)-4- (trifluoromethyl) phenoxy) piperidine-1-carbonyl)- 1H-pyrazol-3-

(Methanol-d4) δ 8.10 (d, J = 2.8 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.08(d, J = 2.0 Hz, 1H), 6.99-6.90 (m, 1H), 6.28 (d, J = 2.8 Hz, 1H),4.88-4.80 (m, 2H), 4.79-4.69 (m, 1H), 552.2 yl)methane- 4.37-4.20 (m,1H), sulfonamide 4.20-4.09 (m, 1H), 4.04-3.91 (m, 1H), 3.91-3.80 (m,1H), 3.16 (s, 3H), 3.12- 3.02 (m, 2H), 2.90-2.80 (m, 2H), 2.39-2.26 (m,1H), 2.12-2.01 (m, 1H), 2.01-1.84 (m, 4H) 211 N-(1-(4-(4- Chloro-3-(4-cyano- piperidin-1- yl)benzyl) piperazine- 1-carbonyl)- 1H-pyrazol-3-yl)methane- sulfonamide

δ 8.01 (s, 1H), 7.39-7.24 (m, 1H), 7.03 (s, 1H), 7.01- 6.90 (m, 1H),6.29 (s, 1H), 4.90 (s, 1H), 3.94-3.73 (m, 4H), 3.50 (s, 2H), 3.27-3.18(m, 2H), 3.13 (s, 3H), 3.00 (s, 2H), 2.91-2.81 506.2 (m, 1H), 2.57-2.46(m, 4H), 2.18-2.00 (m, 4H) 212 N-(1-(4-(4- Chloro-3- fluorobenzyl)piperazine- 1-carbonyl)- 1H-pyrazol- 3-yl)methane- sulfonamide

δ 7.91 (s, 1H), 7.28-7.19 (m, 1H), 7.11-7.04 (m, 1H), 6.99-6.89 (m, 1H),6.45 (s, 1H), 6.17 (s, 1H), 3.73 (s, 4H), 3.41 (s, 2H), 3.04 (s, 3H),2.42 (s, 4H) 416.1 213 N-(1-(4-(4- Chloro-3- (4-isopropyl- piperidin-1-yl)benzyl) piperazine- 1-carbonyl)- 1H-pyrazol-3- yl)methane-sulfonamide

δ 7.93 (s, 1H), 7.23-7.10 (m, 1H), 6.91 (s, 1H), 6.85- 6.72 (m, 1H),6.19 (s, 1H), 3.74 (s, 4H), 3.41 (s, 2H), 3.39-3.24 (m, 2H), 3.03 (s,3H), 2.55- 2.35 (m, 6H), 1.75-1.62 (m, 2H), 1.50-1.30 (m, 3H), 523.21.13-0.99 (m, 1H), 0.93-0.77 (m, 6H) 214 N-(1-(4-(4- Chloro-3-(trifluoromethyl) benzyl) piperazine- 1-carbonyl)- 1H-pyrazol-3-yl)methane- sulfonamide

δ 7.95 (s, 1H), 7.58 (s, 1H), 7.38 (s, 2H), 6.22 (s, 1H), 3.76 (s, 4H),3.47 (s, 2H), 3.05 (s, 3H), 2.50-2.39 (m, 4H) 466.1 215 (R)-N-(1-(4-(4-Chloro-3- cyclopentyl- benzyl)-3- methyl- piperazine- 1-carbonyl)-1H-pyrazol-3- yl)methane- sulfonamide

δ 8.10-8.04 (m, 1H), 7.35-7.28 (m, 1H), 7.24 (s, 1H), 7.19-7.04 (m, 1H),7.03-6.79 (m, 1H), 6.36-6.30 (m, 1H), 4.28-4.06 (m, 2H), 4.03-3.93 (m,1H), 3.53-3.35 (m, 2H), 3.32-3.17 (m, 2H), 3.15 (s, 3H), 2.83- 480.22.70 (m, 1H), 2.68-2.54 (m, 1H), 2.32-2.18 (m, 1H), 2.17-2.05 (m, 2H),1.90-1.67 (m, 4H), 1.60-1.53 (m, 2H), 1.19 (d, J = 4.8 Hz, 3H) 216(S)-N-(1-(4- (4-Chloro-3- cyclopentyl- benzyl)-3- methyl- piperazine-1-carbonyl)- 1H-pyrazol-3- yl)methane- sulfonamide

δ 8.10-8.04 (m, 1H), 7.35-7.28 (m, 1H), 7.24 (s, 1H), 7.19-7.04 (m, 1H),7.03-6.79 (m, 1H), 6.36-6.30 (m, 1H), 4.28-4.06 (m, 2H), 4.03-3.93 (m,1H), 3.53-3.35 (m, 2H), 3.32-3.17 (m, 2H), 3.15 (s, 3H), 2.83- 480.22.70 (m, 1H), 2.68-2.54 (m, 1H), 2.32-2.18 (m, 1H), 2.17-2.05 (m, 2H),1.90-1.67 (m, 4H), 1.60-1.53 (m, 2H), 1.19 (d, J = 3.2 Hz, 3H) 217N-(1-(4-((4- Chloro-3- methylbenzyl) (methyl)amino)- 4-methyl-piperidine- 1-carbonyl)- 1H-pyrazol-3- yl)acetamide

δ 8.02 (d, J = 2.8 Hz, 1H), 7.76 (br, 1H), 7.28 (s, 1H), 7.26-7.16 (m,2H), 6.90 (d, J = 2.8 Hz, 1H), 3.97 (br, 2H), 3.79 (br, 2H), 3.51 (br,2H), 2.39 (br, 3H), 2.20 (br, 3H), 2.10 (s, 3H), 418.2 2.04 (br, 2H),1.61 (br, 2H), 1.07 (br, 3H) 218 N-(1-(4-(4- Fluoro-3-(trifluoromethoxy) benzyl) piperazine- 1-carbonyl)- 1H-pyrazol-3-yl)methane- sulfonamide

δ 7.96 (s, 1H), 7.27-7.22 (m, 1H), 7.19-7.14 (m, 1H), 7.12-7.05 (m, 1H),6.24 (s, 1H), 3.83- 3.70 (m, 4H), 3.44 (s, 2H), 3.06 (s, 3H), 2.49-2.40(m, 4H) 466.1 219 N-(1-(4-(2- Chloro-3- (trifluoromethyl) benzyl)piperazine- 1-carbonyl)- 1H-pyrazol-3- yl)methane- sulfonamide

δ 8.03 (s, 1H), 7.77-7.69 (m, 1H), 7.69-7.63 (m, 1H), 7.43-7.33 (m, 1H),6.42 (s, 1H), 6.29 (s, 1H), 3.86 (s, 4H), 3.72 (s, 2H), 3.16 (s, 3H),2.70- 2.54 (m, 4H) 466.1 220 N-(1-(4-(2- Methyl-3- (trifluoromethyl)benzyl) piperazine- 1-carbonyl)- 1H-pyrazol-3- yl)methane- sulfonamide

δ 8.01 (s, 1H), 7.58 (s, 1H), 7.44 (s, 1H), 7.25 (s, 1H), 6.28 (s, 1H),5.65 (s, 1H), 3.82 (s, 4H), 3.55 (s, 2H), 3.15 (s, 3H), 2.57-2.51 (m,4H), 2.50 (s, 3H) 446.1 221 N-(1-(4-(3- (Cyclopropyl- methoxy)-4-(difluoro- methoxy) benzyl) piperazine- 1-carbonyl)- 1H-pyrazol-3-yl)methane- sulfonamide

δ 7.85 (s, 1H), 7.03-6.88 (m, 1H), 6.81 (s, 1H), 6.76- 6.65 (m, 1H),7.2- 7.1, 6.50-6.40, 6.3-6.2 (m, 1H), 6.20-6.06 (m, 1H), 5.23 (s, 1H),3.79- 3.59 (m, 6H), 3.35 (s, 2H), 2.98 (s, 3H), 2.37 (s, 4H), 500.21.23-1.02 (m, 1H), 0.58-0.44 (m, 2H), 0.28-0.13 (m, 2H) 222 N-(1-(4-(4-Fluoro-3- phenoxy- benzyl) piperazine- 1-carbonyl)- 1H-pyrazol-3-yl)methane- sulfonamide

δ 8.00 (s, 1H), 7.41-7.31 (m, 2H), 7.21-7.05 (m, 4H), 7.04-6.94 (m, 2H),6.28 (s, 1H), 5.77 (s, 1H), 3.87-3.70 (m, 4H), 3.48 (s, 2H), 3.12 (s,3H), 2.60-2.44 (m, 4H) 474.2 223 (S)-N-(1-(4- ((5-Chloro- 4-(4-fluoro-piperidin-1- yl)pyridin-2- yl)methyl)- 3-methyl- piperazine-1-carbonyl)- 1H-pyrazol-3-

(Methanol-d4) δ 8.28 (s, 1H), 8.06 (d, J = 2.8 Hz, 1H), 7.22 (s, 1H),6.24 (d, J = 2.8 Hz, 1H), 4.97-4.78 (m, 1H), 4.33-4.12 (m, 2H),4.04-4.01 (m, 1H), 3.49-3.44 (m, 2H), 3.41-3.35 514.3 yl)methane- (m,2H), 3.29-3.24 sulfonamide (m, 3H), 3.15 (s, 3H), 2.85-2.82 (m, 1H),2.71-2.68 (m, 1H), 2.44-2.39 (m, 1H), 2.21-1.99 (m, 4H), 1.19 (d, J =6.4 Hz, 3H) 224 (R)-N-(1-(4- (4-Chloro-3- (pyrrolidin- 1-yl)benzyl)-3-methyl- piperazine- 1-carbonyl)- 1H-pyrazol- 3-yl)methane- sulfonamide

δ 8.05 (d, J = 2.8 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 6.85 (s, 1H), 6.76(d, J = 8.0 Hz, 1H), 6.32 (d, J = 2.8 Hz, 1H), 4.27-4.08 (m, 2H),4.02-3.93 (m, 1H), 3.50-3.35 (m, 5H), 3.29-3.11 (m, 5H), 481.1 2.84-2.75(m, 1H), 2.67-2.56 (m, 1H), 2.30-2.20 (m, 1H), 2.04-1.92 (m, 4H), 1.19(d, J = 6.4 Hz, 3H)

II. Biological Evaluation In Vitro Competitive Activity-Based ProteinProfiling.

Proteomes (mouse brain membrane fraction or cell lysates for mouseassays; human prefrontal cortex or PC3 cell membrane fractions for humanassays) (50 μL, 1.0 or 2.0 mg/mL total protein concentration) werepreincubated with varying concentrations of inhibitors at 37° C. After30 min, FP-Rh or JW912 or HT-01 (1.0 μL, 50 μM in DMSO) was added andthe mixture was incubated for another 30 min at 37° C. Reactions werequenched with SDS loading buffer (15 μL-4×) and run on SDS-PAGE.Following gel imaging, serine hydrolase activity was determined bymeasuring fluorescent intensity of gel bands corresponding to MAGL andFAAH using ImageJ 1.43u software. IC₅₀ data from this assay is shown inTable 1. All compounds in Table 1 were more potent inhibitors of MAGLthan FAAH.

Preparation of Mouse Brain Proteomes from Inhibitor Treated Mice.

Inhibitors were administered to wild-type C57B1/6J by oral gavage in avehicle of polyethylene glycol. Each animal was sacrificed 4 h followingadministration and brain proteomes were prepared and analyzed accordingto previously established methods (See Niphakis, M. J., et al. (2011)ACS Chem. Neurosci. and Long, J. Z., et al. Nat. Chem. Biol. 5:37-44).

Compounds demonstrated activity in the assays described herein asindicated in Table 1.

TABLE 1 MAGL FAAH MAGL FAAH MAGL FAAH MAGL FAAH % inh. % inh. % inh. %inh. IC₅₀ IC₅₀ % inh. % inh. 1 μM 1 μM 1 μM 1 μM (μM) (μM) 5 mg/kg 5mg/kg Ex (human) (human) (mouse) (mouse) (human) (human) (mouse) (mouse)1 A @ D D D 10 μM 2 A D A D 3 A D A D 4 A D A D D D 5 A D A D 6 A D A D7 A D A D 8 A D A D 9 A D A D 10 B @ D D D 10 μM 11 A D A D *** * C D 12A D A D D D 13 A C *** * 14 A D B D *** * D D 15 A D A C 16 A C A C 17 AA A A 18 A A A A *** ** 19 A D A D 20 A D A A *** * 21 A D A D 22 A B AA *** ** C C 23 A A A A *** ** 24 A D A D 25 A D A D *** * 26 A D D D 27D @ D D 10 μM 28 A A A A 29 B @ D D D 10 μM 30 A A A 31 A D A D 32 A D AD A D 33 A A D 34 A A A A *** ** 35 A D A D 36 A A 37 A A 38 A C *** *39 A B *** * A D 40 C B C A 41 D A 42 A A 43 A D A D *** * 44 A A 45 D @D D D 10 μM 46 C @ D D D 10 μM 47 C @ D D D 50 μM 48 C @ D D D 50 μM 49C D B D 50 B D B A 51 A A A A *** ** 52 A D A D *** * 53 A @ D D D 10 μM54 A D A D 55 A D A D 56 A D A D 57 A D A D 58 A D A D A D 59 A D A D 60A D A D 61 C D B D 62 A D A D 63 A D A D *** * C D 64 A D A D 65 A D A D66 A D A D 67 A C A C 68 A D A D 69 A @ D D D 10 μM 70 A D A D 71 A D AD A D 72 A D C B 73 A D A B 74 A D A D *** * 75 A D A D A D 76 A D A D DD 77 B D D D 78 A D A D 79 A D A D D D 80 A D A D A D 81 A D B D 82 A DB D 83 A D A D 84 A D A D 85 A D A D 86 C D C D 87 A D A D D D 88 A D AD 89 A D A D 90 A D A D C D 91 A C A B 92 A D A D 93 A D A D D D 94 A DA D A D 95 A D A D 96 A D A D D D 97 C D C D 98 A D A D D D 99 A D A D100 B D B D 101 A D B D 102 B D D D 103 A D A D D D 104 A D A D D D 105A D A D 106 A D A D D D 107 A D A D 108 A D A D D D 109 A D A D 110 A DA D 111 A D A D 112 A C A A A A 113 A C A A 114 A C C A 115 A C C A 116A D B D 117 A D A D B D 118 A D A D D D 119 A D A D A D 120 A D A D 121A A A A *** ** 122 A D A D 123 A D A D 124 A D A D 125 A D A D D D 126 AD A D 127 A D A D 128 A D A D 129 A D A D 130 A D A D 131 A A A A *** *A A 132 A D A D *** * D D 133 A D A D D D 134 A D A D C D 135 A D A D DD 136 A D A D A D 137 A D A D D D 138 A D A D A D 139 A D A D *** * D D140 C D D D 141 A D A D A D 142 A D A D 143 A D A D D D 144 A D A D 145A A A A *** ** 146 A A A A *** * 147 A D A D 148 A D A D A D 149 A A A A*** ** 150 A C A D *** * D D 151 A D A D 152 A @ 10 μM 153 A D B D 154 AC A A *** * B C 155 A D A A 156 A D A D A D 157 A D A D D D 158 A D A DD D 159 A D A D D D 160 B C D D 161 A D 162 A D D D 163 A D D D 164 A DD D 165 A @ 10 μM 166 A D A A 167 A C A A 168 A B A A A A 169 A B A A BB 170 A B 171 A B 172 A A *** ** 173 A A *** ** 174 A B 175 A A *** 176A A *** A 177 A A 178 A A *** 179 A A *** 180 A A *** 181 A A *** 182 AA *** D 183 A A 184 A A *** 185 A A A 186 A A A 187 A A *** 188 A A A189 A A A 190 A A D 191 A A 192 A A 193 A A 194 B @ D 10 μM 195 A A 196A A 197 A A D 198 A B 199 A A 200 A A 201 A A 202 A A 203 A 204 A 205 A206 A 207 A 208 A *** 209 A A 210 A A 211 A 212 A 213 A 214 A 215 A 216A 217 A 218 A 219 A 220 A 221 A 222 A 223 A A 224 A A *** IC₅₀ is lessthan or equal to 100 nM; ** IC₅₀ is greater than 100 nM and less than 1μM; * IC₅₀ is greater than or equal to 1 μM and less or equal to 10 μM.A = % inhibition is greater than or equal to 75%; B = % inhibition isgreater than or equal to 50% and less than 75%; C = % inhibition isgreater than or equal to 25% and less than 50%; D = % inhibition isgreater than or equal to 0% and less than 25%.

What is claimed is:
 1. A compound of Formula (I):

wherein: R¹ is —N(R²)C(O)R¹⁵ or —N(H)SO₂R¹⁵; R² is H or C₁₋₆alkyl; R³ is

A is N or C(H); X is —O—, —N(R¹⁶)—, or —CH₂N(R¹⁶)CH₂—; Y is —CH₂— or—C(O)—; Z is —S—, —O—, or —N(R²⁰)—; R⁴ is H, halogen, —OR⁷, C₁₋₆alkyl,C₁₋₆alkyl-OH, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,—O—C₃₋₈cycloalkyl, —O—C₃₋₈cycloalkyl-OH, —N(H)—C₁₋₆alkyl-CO₂H, —SO₂R¹⁷,—CO₂R⁸, —C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,—C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, C₁₋₉heteroaryl, whereinC₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,C₆₋₁₀aryl, C₁₋₉heteroaryl are optionally substituted with 1 or 2 R¹⁴; R⁵is H, —CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkoxy, or phenyl;R⁶ is H, halogen, or C₁₋₆alkyl; R⁷ is H, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl,wherein C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, or C₁₋₉heteroaryl areoptionally substituted with 1 or 2 R¹⁴; each R⁸ and each R⁹ areindependently selected from H and C₁₋₆alkyl; or R⁸ and R⁹ together withthe nitrogen to which they are attached are combined to form aheterocycloalkyl ring; R¹⁰ is —O—C₁₋₆haloalkyl, —O—C₁₋₆alkyl-CO₂H,—O—C₃₋₈cycloalkyl, —O—C₃₋₈cycloalkyl-CO₂H, —N(H)—C₁₋₆alkyl-CO₂H, or—SO₂R¹⁷; R¹² is H, halogen, or C₁₋₆alkyl; R¹³ is H or C₁₋₆alkyl; eachR¹⁴ is independently selected from halogen, —OH, oxo, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, —C₁₋₆alkyl-OH, C₃₋₈cycloalkyl, —CO₂R⁸,—C(O)NR⁸R⁹, —C(O)—C₁₋₆alkyl, —C(O)—C₁₋₆alkyl-OH, —SO₂—C₁₋₆alkyl,—N(R⁸)SO₂—C₁₋₆alkyl, and —N(R⁸)C(O)—C₁₋₆alkyl; R¹⁵ is C₁₋₆alkyl orC₃₋₈cycloalkyl; R¹⁶ is H, C₁₋₆alkyl, —C(O)—C₁₋₆alkyl, or —CH₂CO₂H; R¹⁷is C₁₋₆alkyl or C₃₋₈cycloalkyl; R¹⁸ and R¹⁹ are independently selectedfrom H and C₁₋₆alkyl, wherein R¹⁸ and R¹⁹ are not both H; R²⁰ is H orC₁₋₆alkyl; v is 0 or 1; n is 0 or 1; m is 0 or 1; p is 0, 1, or 2; q is0, 1, or 2; and w is 1 or 2; or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof.
 2. Thecompound of claim 1, or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R³ is


3. The compound of claim 2, or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is1, n is 1, p is 1, and w is
 1. 4. The compound of claim 2, or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein m is 0, n is 1, p is 1, and w is
 2. 5. Thecompound of claim 2, or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is1, n is 1, p is 0, and w is
 1. 6. The compound of any one of claims 1-5,or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein A is C(H).
 7. Thecompound of any one of claims 1-5, or a solvate, hydrate, tautomer,N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof,wherein A is N.
 8. The compound of claim 1, or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R³ is


9. The compound of claim 8, or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is1, n is 1, q is 1, and p is
 1. 10. The compound of claim 8, or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein m is 0, n is 1, q is 2, and p is
 1. 11.The compound of claim 8, or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is1, n is 1, q is 0, and p is
 2. 12. The compound of claim 8, or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein m is 1, n is 1, q is 1, and p is
 0. 13.The compound of any one of claims 8-12, or a solvate, hydrate, tautomer,N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof,wherein Z is —S—.
 14. The compound of any one of claims 8-12, or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein Z is —N(H)—.
 15. The compound of anyone of claims 1-14, or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein Y is—CH₂—.
 16. The compound of any one of claims 1-14, or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein Y is —C(O)—.
 17. The compound of claim 1, or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R³ is


18. The compound of claim 1, or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R³ is


19. The compound of any one of claims 1-18, or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁶ is H.
 20. The compound of claim 1, or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is


21. The compound of claim 1, or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R³ is


22. The compound of claim 20 or claim 21, or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein Z is —S—.
 23. The compound of claim 20 or claim 21, ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein Z is —N(H)—.
 24. The compound of anyone of claims 1-23, or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹³is H.
 25. The compound of any one of claims 1-24, or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹² is H.
 26. The compound of claim 1, or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is


27. The compound of claim 26, or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹³is H.
 28. The compound of claim 26, or a solvate, hydrate, tautomer,N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof,wherein R¹³ is —CH₃.
 29. The compound of any one of claims 26-28, or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R¹² is H.
 30. The compound of claim 1,or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R³ is


31. The compound of any one of claims 26-30, or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein v is
 0. 32. The compound of any one of claims 26-30, ora solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein v is
 1. 33. The compound of any one ofclaims 26-32, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein X is —O—.
 34. Thecompound of any one of claims 26-32, or a solvate, hydrate, tautomer,N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof,wherein X is —N(CH₃)—.
 35. The compound of claim 1, or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R³ is


36. The compound of any one of claims 26-35, or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein A is C(H).
 37. The compound of any one of claims 26-35,or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein A is N.
 38. Thecompound of claim 1, or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R³ is


39. The compound of claim 38, or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁸is C₁₋₆alkyl.
 40. The compound of claim 39, or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹⁻⁸ is —CH₃ and R¹⁹ is H.
 41. The compound of claim38, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁹ is C₁₋₆alkyl. 42.The compound of claim 41, or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R¹⁸is H and R¹⁹ is —CH₃.
 43. The compound of any one of claims 26-42, or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁶ is H.
 44. The compound of any one ofclaims 1-43, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is halogen, —OR⁷,C₁₋₆alkyl-OH, —N(H)—C₁₋₆alkyl-CO₂H, C₂₋₆alkynyl, C₁₋₆haloalkyl, —CO₂R⁸,—C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl, orC₁₋₉heteroaryl, wherein C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₆₋₁₀aryl,or C₁₋₉heteroaryl are optionally substituted with 1 or 2 R¹⁴.
 45. Thecompound of any one of claims 1-44, or a solvate, hydrate, tautomer,N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof,wherein R⁴ is halogen, —OR⁷, —N(H)—C₁₋₆alkyl-CO₂H, C₁₋₆haloalkyl,—C(O)NR⁸R⁹, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, or C₁₋₉heteroaryl,wherein C₂₋₉heterocycloalkyl or C₁₋₉heteroaryl are optionallysubstituted with 1 or 2 R¹⁴.
 46. The compound of any one of claims 1-45,or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is halogen.
 47. Thecompound of claim 46, or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁴ is—Cl.
 48. The compound of any one of claims 1-45, or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is C₁₋₆haloalkyl.
 49. The compound of claim 46, or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —CF₃.
 50. The compound of any oneof claims 1-45, or a solvate, hydrate, tautomer, N-oxide, stereoisomer,or pharmaceutically acceptable salt thereof, wherein R⁴ is—N(H)—C₁₋₆alkyl-CO₂H.
 51. The compound of any one of claims 1-45, or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁴ is —OR⁷.
 52. The compound of claim51, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁷ is unsubstitutedC₃₋₈cycloalkyl or C₆₋₁₀aryl optionally substituted with halogen.
 53. Thecompound of any one of claims 1-45, or a solvate, hydrate, tautomer,N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof,wherein R⁴ is C₂₋₉heterocycloalkyl optionally substituted with 1 or 2R¹⁴.
 54. The compound of claim 53, or a solvate, hydrate, tautomer,N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof,wherein R⁴ is an unsubstituted C₂₋₉heterocycloalkyl.
 55. The compound ofclaim 53, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ isC₂₋₉heterocycloalkyl substituted with 1 or 2 R¹⁴.
 56. The compound ofclaim 53, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is


57. The compound of any one of claims 1-45, or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is C₁₋₉heteroaryl optionally substituted with 1 or 2R¹⁴.
 58. The compound of claim 57, or a solvate, hydrate, tautomer,N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof,wherein R⁴ is an unsubstituted C₁₋₉heteroaryl.
 59. The compound of claim57, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁴ is C₂₋₉heteroarylsubstituted with 1 or 2 R¹⁴.
 60. The compound of claim 57, or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁴ is


61. The compound of any one of claims 1-45, or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁴ is —C(O)NH₂.
 62. The compound of claim 1, or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R³ is


63. The compound of claim 1, or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R³ is


64. The compound of claim 62 or claim 63, or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹⁰ is —O—C₁₋₆alkyl-CO₂H.
 65. The compound of claim 64,or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁰ is —OCH₂CO₂H or—OCH₂CH₂CH₂CO₂H.
 66. The compound of claim 62 or claim 63, or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹⁰ is, —N(H)—C₁₋₆alkyl-CO₂H.
 67. The compound ofclaim 66, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹⁰ is —N(H)CH₂CO₂H,—N(H)CH₂CH₂CO₂H, or —N(H)CH₂CH₂CH₂CO₂H.
 68. The compound of any one ofclaims 62-67, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁶ is H.
 69. Thecompound of any one of claims 1-68, or a solvate, hydrate, tautomer,N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof,wherein R⁵ is H, —CN, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, orC₁₋₆haloalkoxy.
 70. The compound of claim 69, or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R⁵ is H.
 71. The compound of claim 69, or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R⁵ is halogen.
 72. The compound of claim 71, or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R⁵ is —Cl.
 73. The compound of claim69, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R⁵ is C₁₋₆haloalkyl.74. The compound of claim 73, or a solvate, hydrate, tautomer, N-oxide,stereoisomer, or pharmaceutically acceptable salt thereof, wherein R⁵ is—CF₃.
 75. The compound of any one of claims 1-74, or a solvate, hydrate,tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable saltthereof, wherein R¹ is —N(R²)C(O)R¹⁵.
 76. The compound of claim 75, or asolvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceuticallyacceptable salt thereof, wherein R² is H.
 77. The compound of any one ofclaims 1-74, or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof, wherein R¹ is —N(H)SO₂R¹⁵. 78.The compound of any one of claims 1-77, or a solvate, hydrate, tautomer,N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof,wherein R¹⁵ is C₁₋₆alkyl.
 79. The compound of claim 78, or a solvate,hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptablesalt thereof, wherein R¹⁵ is —CH₃.
 80. A compound selected from:

or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof.
 81. A compound selected from:

or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof.
 82. A compound selected from:

or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof.
 83. A compound selected from:

or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof.
 84. A compound selected from:

or a solvate, hydrate, tautomer, N-oxide, stereoisomer, orpharmaceutically acceptable salt thereof.
 85. A pharmaceuticalcomposition comprising a compound of any one of claims 1-84, or asolvate, hydrate, tautomer, N-oxide, or a pharmaceutically acceptablesalt thereof, and at least one pharmaceutically acceptable excipient.86. A method of treating pain in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound of any one of claims 1-84, or a solvate, hydrate, tautomer,N-oxide, or a pharmaceutically acceptable salt thereof.
 87. The methodof claim 86, wherein the pain is neuropathic pain.
 88. The method ofclaim 86, wherein the pain is inflammatory pain.
 89. A method oftreating a disease or disorder in a patient comprising administering tothe patient in need thereof a therapeutically effective amount of acompound of any one of claims 1-84, or a pharmaceutically acceptablesalt or solvate thereof, wherein the disease or disorder is selectedfrom migraine, epilepsy/seizure disorder, neuromyelitis optica (NMO),Tourette syndrome, persistent motor tic disorder, persistent vocal ticdisorder, and abdominal pain associated with irritable bowel syndrome.90. The method of claim 89, wherein the disease or disorder is migraine.91. The method of claim 89, wherein the disease or disorder isepilepsy/seizure disorder.
 92. The method of claim 89, wherein thedisease or disorder is neuromyelitis optica (NMO).
 93. The method ofclaim 89, wherein the disease or disorder is Tourette syndrome.
 94. Themethod of claim 89, wherein the disease or disorder is persistent motortic disorder.
 95. The method of claim 89, wherein the disease ordisorder is persistent vocal tic disorder.
 96. The method of claim 89,wherein the disease or disorder is abdominal pain associated withirritable bowel syndrome.